Spirocycloheptanes as inhibitors of rock

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, or pharmaceutically-acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/797,414, filed Jul. 13, 2015, now allowed, which is entitled topriority pursuant to 35 U.S.C. § 119(e) to U.S. provisional patentapplication No. 62/024,555, filed on Jul. 15, 2014, which isincorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to novel spirocycloheptanes andtheir analogues thereof, which are inhibitors of Rho kinases,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of disorders associated with aberrantRho kinase activity.

BACKGROUND OF THE INVENTION

Rho-Kinase (ROCK) is a member of the serine-threonine protein kinasefamily. ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. etal., EMBO J., 15:1885-1893 (1996)), ROCK has been identified as aneffector molecule of RhoA, a small GTP-binding protein (G protein) thatplays a key role in multiple cellular signaling pathways. ROCK and RhoAare ubiquitously expressed across tissues. The RhoA/ROCK signalingpathway is involved in a number of cellular functions, such as ACTIN®organization, cell adhesion, cell migration, and cytokinesis (Riento, K.et al., Nat. Rev. Mol. Cell Biol., 4:446-456 (2003)). It is alsodirectly involved in regulating smooth muscle contraction (Somlyo, A.P., Nature, 389:908-911 (1997)). Upon activation of its receptor, RhoAis activated, and, in turn, it activates ROCK. Activated ROCKphosphorylates the myosin-binding subunit of myosin light chainphosphatase, which inhibits activity of the phosphatase and leads tocontraction. Contraction of the smooth muscle in the vasculatureincreases blood pressure, leading to hypertension.

There is considerable evidence in the literature that the Rho A/ROCKsignaling pathway plays an important role in signal transductioninitiated by several vasoactive factors, for example angiotensin II(Yamakawa, T. et al., Hypertension, 35:313-318 (2000)), urotension II(Sauzeau, V. et al., Circ. Res., 88:1102-1104 (2001)), endothelin-1(Tangkijvanich, P. et al., Hepatology, 33:74-80 (2001)), serotonin(Shimokawa. H., Jpn. Circ. J, 64:1-12 (2000)), norepinephrine (Martinez,M. C. et al., Am. J. Physol., 279:H1228-H1238 (2000)) andplatelet-derived growth factor (PDGF) (Kishi, H. et al., J. Biochem.,128:719-722 (2000)). Many of these factors are implicated in thepathogenesis of cardiovascular disease.

Additional studies in the literature, some using the known ROCKinhibitors fasudil (Asano, T. et al., J. Pharmacol. Exp. Ther.,241:1033-1040 (1987)) or Y-27632 (Uehata, M. et al., Nature, 389:990-994(1997)) further illustrate the link between ROCK and cardiovasculardisease. For example, ROCK expression and activity have been shown to beelevated in spontaneously hypertensive rats, suggesting a link to thedevelopment of hypertension in these animals (Mukai, Y. et al., FASEBJ., 15:1062-1064 (2001)). The ROCK inhibitor Y-27632 (Uehata, M. et al.,Nature, ibid.) was shown to significantly decrease blood pressure inthree rat models of hypertension, including the spontaneouslyhypertensive rat, renal hypertensive rat and deoxycortisone acetate salthypertensive rat models, while having only a minor effect on bloodpressure in control rats. This reinforces the link between ROCK andhypertension.

Other studies suggest a link between ROCK and atherosclerosis. Forexample, gene transfer of a dominant negative form of ROCK suppressedneointimal formation following balloon injury in porcine femoralarteries (Eto, Y. et al., Am. J. Physiol. Heart Circ. Physiol.,278:H1744-H1750 (2000)). In a similar model, ROCK inhibitor Y-27632 alsoinhibited neointimal formation in rats (Sawada, N. et al., Circulation,101:2030-2033 (2000)). In a porcine model of IL-1 beta-induced coronarystenosis, long term treatment with the ROCK inhibitor fasudil was shownto progressively reduce coronary stenosis, as well as promote aregression of coronary constrictive remodeling (Shimokawa. H. et al.,Cardiovasc. Res., 51:169-177 (2001)).

Additional investigations suggest that a ROCK inhibitor would be usefulin treating other cardiovascular diseases. For example, in a rat strokemodel, fasudil was shown to reduce both the infarct size and neurologicdeficit (Toshima, Y., Stroke, 31:2245-2250 (2000)). The ROCK inhibitorY-27632 was shown to improve ventricular hypertrophy, fibrosis andfunction in a model of congestive heart failure in Dahl salt-sensitiverats (Kobayashi, N. et al., Cardiovasc. Res., 55:757-767 (2002)).

Other animal or clinical studies have implicated ROCK in additionaldiseases including coronary vasospasm (Shimokawa, H. et al., Cardiovasc.Res., 43:1029-1039 (1999)), cerebral vasospasm (Sato, M. et al., Circ.Res., 87:195-200 (2000)), ischemia/reperfusion injury (Yada. T. et al.,J. Am. Coll. Cardiol., 45:599-607 (2005)), pulmonary hypertension(Fukumoto, Y. et al., Heart, 91:391-392 (2005)), angina (Shimokawa, H.et al., J. Cardiovasc. Pharmacol., 39:319-327 (2002)), renal disease(Satoh, S. et al., Eur. J. Pharmacol., 455:169-174 (2002)) and erectiledysfunction (Gonzalez-Cadavid, N. F. et al., Endocrine, 23:167-176(2004)).

In another study, it has been demonstrated that inhibition of theRhoA/ROCK signaling pathway allows formation of multiple competinglamellipodia that disrupt the productive migration of monocytes(Worthylake, R. A. et al., J. Biol. Chem., 278:13578-13584 (2003)). Ithas also been reported that small molecule inhibitors of Rho Kinase arecapable of inhibiting MCP-1 mediated chemotaxis in vitro (Iijima, H.,Bioorg. Med. Chem., 15:1022-1033 (2007)). Due to the dependence ofimmune cell migration upon the RhoA/ROCK signaling pathway one wouldanticipate inhibition of Rho Kinase should also provide benefit fordiseases such as rheumatoid arthritis, psoriasis, and inflammatory boweldisease.

The above studies provide evidence for a link between ROCK andcardiovascular diseases including hypertension, atherosclerosis,restenosis, stroke, heart failure, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension andangina, as well as renal disease and erectile dysfunction. Given thedemonstrated effect of ROCK on smooth muscle. ROCK inhibitors may alsobe useful in other diseases involving smooth muscle hyper-reactivity,including asthma and glaucoma (Shimokawa, H. et al., Arterioscler.Thromb. Vasc. Biol., 25:1767-1775 (2005)). Furthermore, Rho-kinase hasbeen indicated as a drug target for the treatment of various otherdiseases, including airway inflammation and hyperresponsiveness (Henry,P. J. et al., Pulm. Pharmacol Ther., 18:67-74 (2005)), cancer (Rattan,R. et al., J. Neurosci. Res., 83:243-255 (2006); Lepley, D. et al.,Cancer Res., 65:3788-3795 (2005)), fibrotic diseases (Jiang, C. et al.,Int. J Mol. Sci., 13:8293-8307 (2012); Zhou, L. et al., Am. J. Nephrol.,34:468-475 (2011)), as well as neurological disorders, such asspinal-cord injury, Alzheimer's disease, multiple sclerosis, stroke andneuropathic pain (Mueller. B. K. et al., Nat. Rev. Drug Disc., 4:387-398(2005); Sun, X. et al., J. Neuroimmunol., 180:126-134 (2006)).

There remains an unmet medical need for new drugs to treatcardiovascular disease. In the 2012 update of Heart Disease and StrokeStatistics from the American Heart Association (Circulation, 125:e2-e220(2012)), it was reported that cardiovascular disease accounted for 32.8%of all deaths in the U.S., with coronary heart disease accounting for ˜1in 6 deaths overall in the U.S. Contributing to these numbers, it wasfound that ˜33.5% of the adult U.S. population was hypertensive, and itwas estimated that in 2010˜6.6 million U.S. adults would have heartfailure. Therefore, despite the number of medications available to treatcardiovascular diseases (CVD), including diuretics, beta blockers,angiotensin converting enzyme inhibitors, angiotensin blockers andcalcium channel blockers, CVD remains poorly controlled or resistant tocurrent medication for many patients.

Although there are many reports of ROCK inhibitors under investigation(see, for example, US 2012/0122842 A1, US 2010/0041645 A1, US2008/0161297 A1, and Hu, E. et al., Exp. Opin. Ther. Targets, 9:715-736(2005)), fasudil is the only marketed ROCK inhibitor at this time. Ani.v. formulation was approved in Japan for treatment of cerebralvasospasm. There remains a need for new therapeutics, including ROCKinhibitors, for the treatment of cardiovascular diseases, cancer,neurological diseases, renal diseases, fibrotic diseases, bronchialasthma, erectile dysfunction, and glaucoma.

SUMMARY OF THE INVENTION

The present invention provides novel spirocycloheptanes, theiranalogues, including stereoisomers, tautomers,pharmaceutically-acceptable salts, or solvates thereof, which are usefulas selective inhibitors of Rho kinases.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically-acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of conditions associated with aberrant ROCK activity.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a conditionassociated with aberrant ROCK activity.

In another aspect, the present invention is directed to a method oftreating a cardiovascular or related disease which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above. Examples of such diseases that maybe treated include, for example, hypertension, atherosclerosis,restenosis, stroke, heart failure, renal failure, coronary arterydisease, peripheral artery disease, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina,erectile dysfunction and renal disease.

In another aspect, the present invention is directed to a method oftreating diseases involving smooth muscle hyper reactivity includingasthma, erectile dysfunction and glaucoma, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In another aspect, the present invention is directed to a method oftreating diseases mediated at least partially by Rho kinase includingfibrotic diseases, oncology, spinal-cord injury, Alzheimer's disease,multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis,psoriasis and inflammatory bowel disease, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In yet additional aspects, the present invention is directed atpharmaceutical compositions comprising the above-mentioned compounds,processes for preparing the above-mentioned compounds and intermediatesused in these processes.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

Ring A is a 5- to 9-membered bicyclic spiro carbocycle;

Ring B is selected from a C₅₋₆ carbocycle and a 5- to 6-memberedheterocycle;

----- is an optional bond;

M is absent or selected from N and CR¹⁰;

L is selected from —(CR⁴R⁴)₀₋₁—, —(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—,and —NR⁶—;

R¹ is selected from NR⁵R⁵, OR⁵, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and—(CR⁴R⁴)_(n)-4- to 15-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p); wherein saidalkyl, carbocycle, and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H, C₁₋₄ alkyl,CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R¹ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p) andsubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₇ alkyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, CN, OH, CHF₂, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl),—(CH₂)_(n)—NR⁸R⁸, —NHCOH, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl),—S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, —NHCO-carbocycle,—NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₆ alkyl,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(O) C₁₋₄alkyl,—(CH₂)_(n)—C(O)O-alkyl, —(CH₂)_(n)—C(O)OC₁₋₄-alkyl,—(CH₂)_(n)—C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)O-carbocycle,—(CH₂)_(n)—C(O)O-heterocycle, —(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n)SO₂carbocycle, —(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, ═O,CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰)_(n)carbocycle, —O(CHR¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle, wherein said alkyl, alkylene, andheterocycle are substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂,N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl),CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c),COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxy aresubstituted with R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2.

According to one particular embodiment of the present invention, thering A corresponds to a 7-membered bicyclic spiro carbocycle, i.e., aspiro[3.3]heptan-2yl.

According to another particular embodiment of the present invention, thering B corresponds to a 6-membered carbocycle or heterocycle; optionallyunsubstituted 6 membered carbocycle or heterocycle. Typically, the ringB is selected in such way that the following structure

is selected from:

According to another particular embodiment of the present invention, Mis an N moiety.

According to another particular embodiment of the present invention, Lis selected from —OC(O)—, —NR⁶C(O)— and —NR⁶— and typically from—NR⁶C(O)— and —NR⁶—.

According to another particular embodiment of the present invention. R¹is selected from NR⁵R⁵, OR⁵, —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-5- to 10-membered heterocycle, wherein said carbocycle andheterocycle are substituted with 1-4 R⁷. Typically, R¹ is selected fromNR⁵R⁵ or heteroaryl substituted with 1-4 R⁷ particularly 5- to10-membered heterocycle substituted with 1-4 R⁷. For example, R¹ may beselected from

typically, from:

According to another particular embodiment of the present invention, R¹is selected from

According to another embodiment of the present invention, R⁶ is selectedfrom H and C₁₋₄ alkyl and is typically H.

According to one further embodiment of the present invention, R⁷ isselected from H, ═O, halogen, F, Cl, Br, CN, OH, CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, —NR⁸R⁸, —(CH₂)_(n)—NR⁸R⁸, —(CH₂)_(n)—NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —(CH₂)_(n)—CONR⁸R⁸,—(CH₂)_(n)-phenyl and —(CH₂)_(n)-heterocycle or from

Typically, R⁷ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN,OH, CF₃, and —NR⁸R⁸.

According to another embodiment of the present invention, R⁸ isindependently selected from H, CF₃, CD₃, CH₃, C(CH₃)₃,

or alternatively R⁸ and R⁸ are taken together to form

According to one further embodiment of the present invention, R⁹ isindependently selected from F, Cl, OH, NO₂, CHF₂, (CH₂)₀₋₂CF₃, CD₃, CH₃,OC₁₋₄ alkyl, SO₂NH₂ and phenyl substituted with C₁₋₄ alkyl.Alternatively. R⁹ can be selected from CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —NH₂, and a 4- to 10-memberedheterocycle.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

is selected from:

M is selected from N and CR¹⁰;

L is selected from —(CR⁴R⁴)₀₋₁—, —(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—,and —NR⁶—;

R¹ is selected from NR⁵R⁵, OR, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and—(CR⁴R⁴)_(n)-4- to 15-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p); wherein saidalkyl, carbocycle, and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered substituted with 1-4R⁷;

R⁶, at each occurrence, is independently selected from H, C₁₋₄ alkyl,CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R¹ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p) andsubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₆ alkyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH)_(n)—NR⁸R⁸, —NHCOH,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)O C₁₋₄alkyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, ═O,CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c): alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂,N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl),CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c),COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxy aresubstituted with R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R¹ is selected from NR⁵R⁵, OR⁵, —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-5- to 10-membered heterocycle, wherein said carbocycle andheterocycle are substituted with 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₆ alkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCOH,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NHC(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkenyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, andheterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle, wherein said alkyl, alkylene, andheterocycle are substituted with 0-4 R^(b); R^(b), at each occurrence,is independently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c), wherein said alkyl and alkoxy are substituted with R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (II) above.

In another aspect, the present invention provides compounds of Formula(IV):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl), —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl),CONH₂, —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—(CH₂)_(n)NHCO(C₁₋₄ alkyl), —O(CH₂)_(n)heterocycle,—O(CH₂)₂₋₄NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H and C₁₋₄alkyl; alternatively, R^(a) and R^(a) are taken together with thenitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, and —NHCO₂(C₁₋₄ alkyl);and

other variables are as defined in Formula (II) above.

In another aspect the present invention provides compounds of Formula(IV) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, —NR⁸R⁸, C₃₋₆ cycloalkyl, phenyl, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-heterocycle, wherein said alkyl, cycloalkyl, phenyl, andheterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁹, at each occurrence, is independently selected from F, Cl, OH, CN,C₁₋₄ alkyl, C₁₋₄ alkoxy, —(CH₂)NR^(a)R^(a), and a 4- to 10-memberedheterocycle, wherein said alkyl, alkoxyl, and heterocycle aresubstituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), and C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl);

R^(b), at each occurrence, is independently selected from halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂,and —NHCO₂(C₁₋₄ alkyl); and

other variables are as defined in Formula (IV) above.

In another aspect, the present invention provides compounds of Formula(III) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle substituted with 1-4R⁷;

R⁷, at each occurrence, is independently selected from H, halogen. C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, and —NR⁸R⁸;

R⁸, at each occurrence, is independently selected from H and C₁₋₄ alkyl;and

other variables are as defined in Formula (III) above.

In still another aspect, the present invention provides compounds ofFormula (V):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R¹ is heteroaryl substituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c); alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl), CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (II) above.

In still another aspect, the present invention provides compounds ofFormula (VI):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁶ is H; and

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹.

In still another aspect, the present invention provides compounds ofFormula (VII):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR⁰;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4 to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂) C(O)NR^(a)R^(a),C(O)OC₁₋₄alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl,SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle,and —(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰R¹⁰)_(n)carbocycle,—O(CHR¹⁰R¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), 0, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (II) above.

In another aspect, the present invention provides compounds of Formula(VII) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is N;

R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4- to 10-membered heterocycle selected from

wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; and

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VII) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is N;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—NH₂, and a 4- to 10-membered heterocycle; and

other variables are as defined in Formula (VII) above.

In another aspect, the present invention provides compounds of Formula(VIII):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein;

M is selected from N and CH;

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂, F,Cl, Br, C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, CN, OH,CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCOH, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—(CH₂)₁₋₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, S(C₁₋₄ alkyl), —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹ and wherein said carbocycle is selected from

and wherein said heterocycle is selected from

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl. SO₂carbocycle, SO₂heterocycle,—(CH₂)_(n)—NHC(O) C₁₋₄alkyl, SO₂NR^(a)R^(a), —(CH₂)_(n)—C₃₋₆cycloalkyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heterocycle, wherein said alkyl,cycloalkyl, aryl, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁹, at each occurrence, is independently selected from F, Cl, Br, I, OH.═O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a), —(CH₂)CONR^(a)R^(a),—(CH₂)_(n)NHCO(C₁₋₄ alkyl), —O(CH₂)_(n)heterocycle,—O(CH₂)₂₋₄NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H and C₁₋₄alkyl; alternatively. R^(a) and R^(a) are taken together with thenitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂, N(C₁₋₄alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl),—CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂,and —NHCO₂(C₁₋₄ alkyl), wherein said alkyl and alkoxy are substitutedwith R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (III) above.

In another aspect, the present invention provides compounds of Formula(VIII):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CH;

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, F, Cl, Br,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,—(CH₂)_(n)—CONR⁸R⁸, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-heterocycleselected from

R⁸, at each occurrence, is independently selected from H, CF₃, CD₃, CH₃,C(CH₃)₃,

alternatively, R⁸ and R⁸ are taken together to form

and

R⁹, at each occurrence, is independently selected from F, Cl, OH, NO₂,CHF₂, (CH₂)₀₋₂CF₃, CD₃, CH₃, OC₁₋₄ alkyl, SO₂NH₂, and phenyl substitutedwith C₁₋₄ alkyl.

In another aspect, the present invention provides compounds of Formula(Ia):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

Ring A is a 5- to 9-membered bicyclic spiro carbocycle;

Ring B is selected from a C₅₋₆ carbocycle and a 5- to 6-memberedheterocycle;

----- is an optional bond;

L is selected from —(CR⁴R⁴)₀₋₁—, —(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—,and —NR⁶—;

R¹ is selected from NR⁵R⁵, OR⁵, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and—(CR⁴R⁴)_(n)-4- to 15-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p); wherein saidalkyl, carbocycle, and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH. CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H, C₁₋₄ alkyl,CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R¹ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p) andsubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₇ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, CN, OH,CHF₂, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl),—(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle, —(CH2)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(O) C₁₋₄alkyl,—(CH₂)_(n)—C(O)OC₁₋₄alkyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, ═O,CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰R¹⁰)_(n)carbocycle, —O(CHR¹⁰R¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c); alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂,N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl),CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c),COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxy aresubstituted with R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₄a alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(IIa):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

is selected from:

L is selected from —(CR⁴R⁴)₀₋₁—, —(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—,and —NR⁶—;

R¹ is selected from NR⁵R⁵, OR⁵, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and—(CR⁴R⁴)_(n)-4- to 15-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p); wherein saidalkyl, carbocycle, and heterocycle are substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H, C₁₋₄ alkyl,CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and a heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R¹ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p) andsubstituted with 1-4 R¹;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₆ alkyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(O) C₁₋₄alkyl,—(CH₂)_(n)—C(O)OC₁₋₄alkyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, ═O,CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰R¹⁰)_(n)carbocycle, —O(CHR¹⁰R¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c); alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂,N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl),CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c),COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxy aresubstituted with R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from NR⁵R⁵, OR⁵, —(CH₂)_(n)—C₃₋₁₀ carbocycle, and—(CH₂)_(n)-5- to 10-membered heterocycle, wherein said carbocycle andheterocycle are substituted with 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH)_(n)—CONR⁸R⁸, —O(CH)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c): alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂, N(C₁₋₄alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl),—CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂,—C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c),CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxy are substitutedwith R^(d);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (II) above.

In another aspect, the present invention provides compounds of Formula(IIIa) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle substituted with 1-4R⁷;

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, and —NR⁸R⁸;

R⁸, at each occurrence, is independently selected from H and C₁₋₄ alkyl;and

other variables are as defined in Formula (IIIa) above.

In still another aspect, the present invention provides compounds ofFormula (Va):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is heteroaryl substituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸R⁸—NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, andheterocycle are substituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively. R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle, wherein said alkyl, alkylene, andheterocycle are substituted with 0-4 R^(b).

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R, andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl), C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (II) above.

In still another aspect, the present invention provides compounds ofFormula (VIIa):

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4 to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁸ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 10-membered heterocyclesubstituted with 1-4 R¹;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle, C(O)O-heterocycle,SO₂alkyl, SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c): alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle, wherein said alkyl, alkylene, andheterocycle are substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (IIa) above.

In another aspect, the present invention provides compounds of Formula(VIII) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂, F,Cl, Br, C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, CN, OH,CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCOH, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—(CH₂)₁₋₂NHCO₂(C₄ alkyl), —NHC(O)NR⁸R⁸. S(C₁₋₄ alkyl), —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹ and wherein said carbocycle is selected from

and wherein said heterocycle is selected from

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,—(CH₂)_(n)—NHC(O) C₁₋₄alkyl, SO₂NR^(a)R^(a), —(CH₂)_(n)—C₃₋₆cycloalkyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heterocycle, wherein said alkyl,cycloalkyl, aryl, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁹, at each occurrence, is independently selected from F, Cl, Br, I, OH,═O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—(CH₂)_(n)NHCO(C₁₋₄ alkyl), —O(CH₂)_(n)heterocycle,—O(CH₂)₂₋₄NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H and C₁₋₄alkyl; alternatively, R^(a) and R^(a) are taken together with thenitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂, N(C₁₋₄alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl),—CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂,and —NHCO₂(C₁₋₄ alkyl), wherein said alkyl and alkoxy are substitutedwith R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (VIII) above.

In another aspect, the present invention provides compounds of Formula(VIII) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

M is N;

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, F, Cl, Br,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,—(CH₂)_(n)—CONR⁸R⁸, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-heterocycleselected from

R⁸, at each occurrence, is independently selected from H, CF₃, CD₃, CH₃,C(CH₃)₃,

alternatively, R⁸ and R⁸ are taken together to form

R⁹, at each occurrence, is independently selected from F, Cl, OH, NO₂,CHF₂, (CH₂)₀₋₂CF₃, CD₃, CH₃, OC₁₋₄ alkyl, SO₂NH₂, and phenyl substitutedwith C₁₋₄ alkyl; and

other variables are as defined in Formula (VIII) above.

In another aspect, the present invention provides compounds of Formula(Va) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ and R⁶ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —(CH₂)_(n)-carbocycle,and —(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), andCO₂H, CO₂(C₁₋₄ alkyl);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2; and

other variables are as defined in Formula (IIa) above.

In another aspect, the present invention provides compounds of Formula(IX) or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein:

R¹ is selected from NR⁵R⁵, and a 5- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R³, at each occurrence, is independently selected from halogen and C₁₋₆alkyl;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle substituted with 1-4R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl. SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, CN,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c); alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2.

In another aspect the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides a compound selectedfrom the group consisting of:

-   N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indene-2-carboxamide;-   4-(dimethylamino)-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   2-(naphthalen-1-yl)-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]acetamide;-   2-(naphthalen-2-yl)-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]acetamide;-   1-methyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-phenylpropanamide;-   N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide;-   3-methyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-4-carboxamide;-   1-tert-butyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-4-carboxamide;-   5-methyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide;-   1-(2,2-difluoroethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-methyl-N-[(aS)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[(aS)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide;-   1-(2,2-difluoroethyl)-N-[(aS)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-4-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide;-   1-(cyclopropylmethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   3-cyclopropyl-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;-   5-cyclopropyl-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-cyclopropyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   5-(difluoromethoxy)-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-cyclopropyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   6-fluoro-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2,2-difluoroethyl)-3-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2-(piperidin-1-yl)-1,3-thiazole-5-carboxamide;-   4-methyl-2-(morpholin-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2-(pyrrolidin-1-yl)-1,3-thiazole-5-carboxamide;-   2-[(3S)-3-fluoropyrrolidin-1-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-[(3R)-3-fluoropyrrolidin-1-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-[(3    S)-3-cyanopyrrolidin-1-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-[(3R)-3-cyanopyrrolidin-1-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   rel-2-[(1S,5R)-2-azabicyclo[3.1.0]hexan-2-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-(3,3-difluoropyrrolidin-1-yl)-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-(cyclopropylamino)-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   4-(aR)-{6-[(5-phenyl-1,3,4-thiadiazol-2-yl)amino]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one,-   4-(aR)-{6-[5-phenyl-1,3-oxazol-2-yl)amino]spiro[3.3]heptan-2-yl}-1,2-dihydrophtbalazin-1-one;-   4-(aR)-{6-[(phthalazin-1-yl)amino]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one,-   4-[6-(2,3-dihydro-1H-indole-1-carbonyl)spiro[3.3]heptan-2-yl]-1,2-dihydrophthalazin-1-one;-   4-[6-(2,3-dihydro-1H-isoindole-2-carbonyl)spiro[3.3]heptan-2-yl]-1,2-dihydrophtbalazin-1-one;-   N-(5-methyl-1,3,4-thiadiazol-2-yl)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptane-2-carboxamide;-   N-(5-methyl-1,2-oxazol-3-yl)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptane-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   4-{6-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one,-   2-[(3R)-3-fluoropyrrolidin-1-yl]-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   2-(3,3-difluoropyrrolidin-1-yl)-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   2-[(3    S)-3-cyanopyrrolidin-1-yl]-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   2-[(3R)-3-cyanopyrrolidin-1-yl]-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   2-[(3,3-difluorocyclobutyl)amino]-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   2-[(3S)-3-fluoropyrrolidin-1-yl]-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-4-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2-[(2    S)-2-(trifluoromethyl)pyrrolidin-1-yl]-1,3-thiazole-4-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1,3-thiazole-4-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-5-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-fluoro-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(morpholin-4-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   2-(morpholin-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2-(pyrrolidin-1-yl)-1,3-thiazole-5-carboxamide;-   N-[(aR)-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1,2-benzoxazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-v    l]-1H-indole-3-carboxamide;-   5-[2-(morpholin-4-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-(2-hydroxy-3-methoxypropoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(morpholin-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-(2-hydroxyethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,1-benzoxazole-3-carboxamide;-   6-(difluoromethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2,2-difluoroethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[2-(1H-pyrazol-1-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(4,4-difluoropiperidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[2-(pyrrolidin-1-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-(morpholin-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(4-methylpiperazin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(3R)-3-fluoropyrrolidin-1-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(3S)-3-fluoropyrrolidin-1-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluoropyrrolidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-fluoroazetidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluoroazetidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-thia-2,5-diazatricyclo[6.4.0.0²,⁶]dodeca-1(8),3,5,9,11-pentaene-4-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[2,1-b][1,3]thiazole-6-carboxamide;-   2-ethyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[2,1-b][1,3,4]thiadiazole-6-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-b]pyridazine-3-carboxamide;-   7-cyclopropyl-6-(2-hydroxy-2-methylpropoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(2,2-difluoroethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxamide;-   1-[(4-methoxyphenyl)methyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   1-(cyclopropylmethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   1-(oxan-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(oxolan-3-yloxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   tert-butyl    N-[2-(4-{[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(3-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   1-benzyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-3-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3,7-dicarboxamide;-   7-cyano-6-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-7-(methoxymethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamide;-   1-(4-methoxyphenyl)-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,2,3-triazole-4-carboxamide;-   1-(3-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,2,3-triazole-4-carboxamide;-   1-(2-methoxyphenyl)-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,2,3-triazole-4-carboxamide;-   5-(4-fluorophenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,2,4-oxadiazole-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(oxolan-3-yloxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-6-(oxolan-3-yloxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   3-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   6-(benzyloxy)-7-cyclopropyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-7-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   7-cyclopropyl-6-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(2-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,2,3-triazole-4-carboxamide;-   6-(benzyloxy)-7-[(dimethylamino)methyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(1,3-difluoropropan-2-yl)oxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(1,1-dioxo-1λ⁶-thian-4-yl)oxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(4,4-difluorocyclohexyl)oxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(oxan-4-yloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   methyl    3-[(3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}pyrazolo[1,5-a]pyridin-6-yl)oxy]azetidine-1-carboxylate;-   6-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluorocyclobutoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy)-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-phenyl-1H-indazole-3-carboxamide;-   6-(4-cblorophenyl)-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(1-methyl-1H-pyrazol-3-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(1-methyl-1H-pyrazol-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[(E)-2-phenylethenyl]-1H-indazole-3-carboxamide;-   6-[(E)-2-cyclopropylethenyl]-1-(2-hydro-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy)-2-methylpropyl)-6-(6-methoxypyridin-2-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-[(Z)-2-cyclopropylethenyl]-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-bromo-1-(2-hydroxy-2-meth)ylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(4-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-(dimethyl-1,2-oxazol-4-yl)-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-(3-chlorophenyl)-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(2-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(3-methoxyphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-(2,6-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   6-(2-cyanophenyl)-1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(1,2-oxazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-[6-fluoro-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide;-   6-fluoro-N-[6-fluoro-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide;-   N-[6-fluoro-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-cyclopropyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-oxo-1,2-dihydropyridin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-{1-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(1,3-thiazol-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(dimethyl-1H-1,2,3-triazol-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1H-imidazol-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(1H-1,2,4-triazol-1-yl)pyrazolo[15-a]pyridine-3-carboxamide;-   6-(2-methoxyethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(4-oxo-1,4-dihydropyridin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-hydroxyethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(3-fluoroazetidin-1-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(dimethylamino)ethoxy]j-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(azetidin-1-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(2,2-dimethylmorpholin-4-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[2-(4-methylpiperazin-1-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethoxy}-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethoxy}-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[3-(morpholin-4-yl)propyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[3-(pyrrolidin-1-yl)propyl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[3-(dimethylamino)propyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[3-(cyclopropylamino)propyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-hydroxypropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[3-(4,4-difluoropiperidin-1-yl)propyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-hydroxy-3-methylbutyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(morpholin-4-ylmethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(4-methylpiperazin-1-yl)methyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(piperidin-1-ylmethyl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(dimethylamino)methyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-benzyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[15-a]pyridine-3-carboxamide;-   6-[3-(morpholin-4-yl)-3-oxopropyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(3,3,3-trifluoropropyl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-cyanoethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-{[2-(morpholin-4-yl)ethoxy]methyl}-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(methoxymethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-methoxypyrimidin-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[(oxan-4-ylmethoxy)methyl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[(prop-2-en-1-yloxy)methyl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(hydroxymethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-acetyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-hydroxypropan-2-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1,5-dimethyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(I-cyclopropyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[1-(²H₃)methyl-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[1-(propan-2-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(trimethyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-tert-buty    1-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-6-[1-(oxolan-3-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(4-bromophenyl)-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   1-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   1-{4-[1-(²H₃)methyl-1H-pyrazol-4-yl]phenyl}-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   1-[4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   1-{4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]phenyl}-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   1-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl}-3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]urea;-   3-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-[4-(trimethyl-1H-pyrazol-4-yl)phenyl]urea,-   5-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-(trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-indole-1-carboxamide;-   5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   5-(1-tert-butyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-[1-(oxolan-3-yl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-[l-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-5-(trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-[1-methyl-3-(trifluormethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   N-[(aR)₄-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-(1-tert-butyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   3,3-dimethyl-N-[(aR)₄-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H,2H,3H-pyrrolo[2,3-b]pyridine-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxamide;-   5-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-6-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carboxamide;-   5-(dimethylsulfamoyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   3-(morpholin-4-ylmethyl)-N-[(aR)₄-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-1-carboxamide;-   2-(4-methylphenyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxamide;-   5-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidine]-1-carboxamide;-   N,1-dimethyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   N-ethyl-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   2-methyl-1-[(3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}pyrazolo[1,5-a]pyridin-6-yl)oxy]propan-2-yl    2-aminoacetate;-   2-methyl-1-[(3-{[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}pyrazolo[1,5-a]pyridin-6-yl)oxy]propan-2-yl    (2S)-2-amino-3-methylbutanoate;-   2-methyl-1-[(3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl})pyrazolo[1,5-a]pyridin-6-yl)oxy]propan-2-yl    (2S)-2-aminopropanoate;-   6-(2-hydroxy-2-methylpropoxy)-N-[6-(1-oxo-1,2-dihydroisoquinolin-4-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   tert-butyl    3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4H,5H,6H,    7H-thieno[2,3-c]pyridine-3-carboxamide;-   6-acetyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4H,51-66H,7H-thieno[2,3-c]pyridine-3-carboxamide;-   methyl    3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate;-   6-methanesulfonyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide;-   6-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,1-benzoxazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-(6-{4-oxo-3H,4H-pyrrolo[1,2-d][1,2,4]triazin-1-yl}spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-N-(6-({4-oxo-3H,4H-pyrrolo[1,2-d][1,2,4]triazin-1-yl}spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-methyl-N-(6-{4-oxo-3H,4H-pyrrolo[1,2-d][1,2,4]triazin-1-yl}spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-N-(6-{8-methyl-4-oxo-3H,4H-pyrrolo[1,2-d][1,2,4]triazin-1-yl}spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   6-[(3,5-dimethylphenyl)amino]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-b]pyridazine-3-carboxamide;-   6-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,1-benzoxazole-3-carboxamide;-   1-ethyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   1-(difluoromethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2,1-benzoxazole-3-carboxamide;-   1-(3-chlorophenyl)-7-oxo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   1-(4-methoxyphenyl)-7-oxo-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-3-carboxamide;-   5-chloro-N-[(aR)₆(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,2-benzoxazole-3-carboxamide;-   6-acetamido-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,2-benzoxazole-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,5-a]pyridine-1-carboxamide;-   5-methoxy-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   7-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridine-2-carboxamide;-   4-chloro-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   2-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-3-carboxamide;-   7-chloro-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   4-chloro-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]thieno[2,3-b]pyrazine-6-carboxamide;-   4-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[15-a]pyridine-3-carboxamide;-   6-chloro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,3-benzodiazole-2-carboxamide;-   5-chloro-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(propan-2-yl)-1H-1,3-benzodiazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,3-benzodiazole-5-carboxamide;-   2-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,3-benzodiazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide;-   4-formamido-3-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   6-chloro-N-[(aR)₆(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-benzothiophene-2-carboxamide;-   6-methoxy-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   2-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-benzoxazole-6-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-6-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-1,3-benzodiazole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   5-(benzyloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   6-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indene-1-carboxamide;-   7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-isoindole-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   N-[(aR)-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]isoquinoline-3-carboxamide;-   7-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   7-chloro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   6-fluoro-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;    N-[(aR)-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]quinoline-2-carboxamide;-   4-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(trifluoromethyl)-1H-indole-2-carboxamide;-   7-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl    1]-1H-indole-2-carboxamide;-   4,7-dimethoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   5-fluoro-7-methanesulfonyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-(1H-pyrazol-1-yl)benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-4-yl)benzamide;-   3-[2-(morpholin-4-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-(1H-pyrazol-4-yl)benzamide;-   3-(4-methyl-1,3-thiazol-2-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   6-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-3-carboxamide;-   N-[(aR)-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(trifluoromethyl)pyridine-3-carboxamide;-   2-hydroxy-6-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-[2-(pyrrolidin-1-yl)ethyl]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-4-(2H-1,2,3,4-tetrazol-5-yl)benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(1H-pyrazol-1-yl)pyridine-3-carboxamide;-   5-chloro-6-hydroxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-1,2,4-triazol-1-yl)benzamide;-   3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   3-methoxy-4-(2-methyl-1,3-thiazol-5-yl)-N—[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide,-   5-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-2-carboxamide;-   3-(1H-imidazol-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   3-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(propan-2-yloxy)benzamide;-   3-(difluoromethoxy)-N-[(aR)-4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   4-ethoxy-5-oxo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3-carboxamide;-   6-(dimethylamino)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-3-yl)benzamide;-   4-(1,3-oxazol-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   4-(1H-imidazol-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-3-(1H-pyrazol-3-yl)benzamide;-   8-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   6-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-3-carboxamide;-   5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-2-(pyridin-4-yl)-1,3-thiazole-4-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-6-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-6-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-5-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-5-(pyrrolidin-1-yl)pyridine-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-5-(trifluoromethyl)pyridine-2-carboxamide;-   5-cyano-6-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-2-carboxamide;-   7-methoxy-3-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-5-carboxamide;-   7-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   5-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   7-(4-methylpiperazin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   8-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide;-   8-chloro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-phenylimidazo[1,2-a]pyridine-3-carboxamide;-   7-(benzyloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   8-chloro-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-(propan-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(4,4-difluoropiperidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(3,3-difluoropyrrolidin-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(3R)-3-fluoropyrrolidin-1-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(3S)-3-fluoropyrrolidin-1-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(3R)-3-hydroxypyrrolidin-1-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(2-hydroxyethyl)(methyl)amino]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(2-methoxyethyl)(methyl)amino]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[2-(morpholin-4-yl)ethoxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(2-hydroxy-2-methylpropyl)(methyl)amino]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(2-hydroxy-2-methylpropoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-[2-(pyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridine-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-7-oxo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H,7H-imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide;-   8-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamide;-   6-fluoro-8-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(difluoromethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   6-fluoro-5-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   6-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(2-hydroxy-2-methylpropyl)amino]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   6-fluoro-7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   6,8-difluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   8-(benzyloxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(methylsulfanyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   4-oxo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-carboxamide;-   3-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-4-yl)benzamide;-   3-cyano-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-4-yl)benzamide;-   3-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-4-yl)benzamide;-   2-methoxy-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-(1H-pyrazol-4-yl)benzamide;-   7-(1-methyl-1H-pyrazol-1-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indole-2-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-6H-isochromeno[4,3-d]pyrimidine-8-carboxamide;-   3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   6-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-3-carboxamide;-   7-acetyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   3-fluoro-4-[1-(²H₃)methyl-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   7-(2-hydroxypropan-2-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-hydroxyethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[(1,1-dioxo-1λ⁶-thian-4-yl)oxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-3-carboxamide;-   7-1(1,3-difluoropropan-2-yl)oxyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(pyridin-2-yloxy)imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3-(propan-2-yl)imidazo[1,5-a]pyridine-1-carboxamide;-   7-(2,2-difluoroethoxy)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(propan-2-yloxy)imidazo[1,2-a]pyridine-3-carboxamide;-   4-(morpholin-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   7-(1-ethyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-[1-(propan-2-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[1-(²H₃)methyl-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   7-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   4-(1-ethyl-1H-pyrazol-4-yl)-3-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   3-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzamide;-   3-fluoro-4-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-fluoro-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   3-fluoro-4-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   5-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-2-carboxamide;-   4-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]benzamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-)yl)spiro[3.3]heptan-2-yl]-7-(pyridine-3-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-7-(pyridin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide;-   7-(2-methyl-1,3-thiazol-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-2-carboxamide;-   7-(2-methyl-1,3-thiazol-5-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   4-[6-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)spiro[3.3]heptan-2-yl]-1,2-dihydrophtbalazin-1-one,-   4-{6-[(4S)-4-benzyl-2-oxoimidazolidin-1-yl]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one,-   4-{6-[(4R)-4-benzyl-2-oxoimidazolidin-1-yl]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one;-   4-{6-[(2-nitrophenyl)amino]spiro[3.3]heptan-2-yl}-1,2-dihydrophthalazin-1-one;-   4-[6-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)spiro[3.3]heptan-2-yl]-1,2-dihydrophtbalazin-1-one,-   4-cyclopropyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;-   3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]pyridine-2-carboxamide;-   6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl    2,3-dihydro-1H-isoindole-2-carboxylate;-   7-methanesulfonyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;-   N-[(aR)-6(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl]pyrazolo[1,5-a]pyrazine-3-carboxamide.-   5-bromo-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indole-2-carboxamide;-   2-methyl-2-[(3-{[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]carbamoyl}pyrazolo[1,5-a]pyridin-6-yl)oxy]propanoic    acid;-   7-(morpholin-4-)yl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide;    and-   7-[(4,4-difluorocyclohexyl)oxy]-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide.

Typically, the present invention is directed to the following compounds:

-   1-methyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   5-methyl-N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   1-(2,2-difluoroethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide;-   3-cyclopropyl-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-5-carboxamide;-   5-cyclopropyl-1-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide;-   4-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)-2-(piperidin-1-yl)thiazole-5-carboxamide;-   2-[(3    S)-3-fluoropyrrolidin-1-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide;-   2-(3,3-difluoropyrrolidin-1-yl)-5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)thiazole-4-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-methoxy-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide;-   6-methoxy-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indole-3-carboxamide;-   6-(2,2-difluoroethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-(1H-pyrazol-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(4-methylpiperazin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((R)-3-fluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((S)-3-fluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-fluoroazetidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluoroazetidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   7-cyclopropyl-6(2-hydroxy-2-methylpropoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6    (3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-7-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(benzyloxy)-7-cyano-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((1,3-fluoropropan-2-yl)oxy)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide.-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6    (3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((4,4-difluorocyclohexyl)oxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3,3-difluorocyclobutoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   1-(2-hydroxy-2-methylpropyl)-6-(2-methoxyphenyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide;-   6-(2-cyanophenyl)-1-(2-hydroxy-2-methylpropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide;-   6-cyclopropyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(thiazol-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-methoxyethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-(2,2-dimethylmorpholino)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-(4-methylpiperazin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-((R)-3-fluoropyrrolidin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(2-((S)-3-fluoropyrrolidin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(3-hydroxy-3-methylbutyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-benzyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(3,3,3-trifluoropropyl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-((allyloxy)methyl)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-((²H₃)meth    1-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-isopropyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[15-a]pyridine-3-carboxamide;-   6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   6-(1-(tert-butyl)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   5-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide;-   5-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide;-   5-(1-(²H₃)methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide;-   2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl    2-aminoacetate;-   (S)-2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl    2-amino-3-methylbutanoate;-   (S)-2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl    2-aminopropanoate;-   6-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)benzo[c]isoxazole-3-carboxamide;-   6-(2-hydroxy-2-methylpropoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)benzo[c]isoxazole-3-carboxamide;-   6-fluoro-7-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indole-2-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-7-(trifluoromethyl)-1H-indole-2-carboxamide;-   7-(4-methylpiperazin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide);-   N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)-7-phenylimidazo[1,2-a]pyridine-3-carboxamide;-   7-(benzyloxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-methoxy-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(4,4-difluoropiperidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(3,3-difluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-((R)-3-fluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-((S)-3-fluoropyrrolidin-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-((2-methoxyethyl)(methyl)amino)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(2-morpholinoethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(2-hydroxy-2-methylpropoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophtbalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   6-fluoro-8-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(difluoromethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   8-(benzyloxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(methylthio)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   3-methoxy-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4-(1H-pyrazol-4-yl)benzamide;-   3-cyano-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4-(1H-pyrazol-4-yl)benzamide;-   3-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4-(1H-pyrazol-4-yl)benzamide;-   7-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-7-(pyridin-2-yloxy)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(2,2-difluoroethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-ethyl-1H-pyrazol-1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-isopropyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   7-(1-(methyl-d3)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-7-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-7-(pyridin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide;-   7-(2-methylthiazol-5-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide;-   7-(2-methylthiazol-5-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;-   4-((aR)-6-(1-oxoisoindolin-2-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one;-   4-((aR)-6-((S)-4-benzyl-2-oxoimidazolidin-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1    (2H)-one;-   4-((aR)-6-((R)-4-benzyl-2-oxoimidazolidin-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one;-   4-((aR)-6-((2-nitrophenyl)amino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one;-   4-((aR)-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one;-   4-cyclopropyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;-   3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.]heptan-2-yl)picolinamide;-   6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl    isoindoline-2-carboxylate;-   7-(methylsulfonyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;    and-   2-methyl-2-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propanoic    acid.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values≤10 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values≤1 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values≤0.1 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values≤0.05 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values≤0.01 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically-acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically-acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, apharmaceutically-acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a condition associated with aberrantROCK activity comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically-acceptable salt, or a solvate thereof. Asused herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a or a stereoisomer, a tautomer, apharmaceutically-acceptable salt, or a solvate thereof. Patients may beselected for prophylaxis therapy based on factors that are known toincrease risk of suffering a clinical disease state compared to thegeneral population. For prophylaxis treatment, conditions of theclinical disease state may or may not be presented yet. “Prophylaxis”treatment can be divided into (a) primary prophylaxis and (b) secondaryprophylaxis. Primary prophylaxis is defined as treatment to reduce orminimize the risk of a disease state in a patient that has not yetpresented with a clinical disease state, whereas secondary prophylaxisis defined as minimizing or reducing the risk of a recurrence or secondoccurrence of the same or similar clinical disease state.

As used herein, “prevention” cover the preventive treatment of asubclinical disease-state in a mammal, particularly in a human, aimed atreducing the probability of the occurrence of a clinical disease-state.Patients are selected for preventative therapy based on factors that areknown to increase risk of suffering a clinical disease state compared tothe general population.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

II. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentanyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro (F), chloro (Cl), bromo (Br), andiodo (I). “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl,pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of“cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclichydrocarbon ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “bicyclic spiro carbocycle” refers to 5- to20-membered polycyclic hydrocarbon group with rings connected throughone common carbon atom (called as spiro atom), wherein one or more ringsmay contain one or more double bonds, but none of the rings has acompletely conjugated pi-electron system. Preferably a bicyclic spirocarbocycle is 6 to 14 membered, more preferably is 7 to 10 membered.Bicyclic spiro carbocycle may be 4-membered/4-membered,4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or5-membered/6-membered spiro ring.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis. R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃. SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically-acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples ofpharmaceutically-acceptable salts include, but are not limited to,mineral or organic acid salts of basic groups such as amines; and alkalior organic salts of acidic groups such as carboxylic acids. Thepharmaceutically-acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically-acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see;

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5. “Design and Application of Prodrugs”. A    Textbook of Drug Design and Development, pp, 113-191,    Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxynethyl or propionyloxymethyl),C₁₋₄alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxcarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain an N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams. “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar.“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “saturated” for saturated, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess. “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution. “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry.“HPLC” for high pressure liquid chromatography. “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”. “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me Methyl-   Et Ethyl-   Pr Propyl-   i-Pr Isopropyl-   Bu Butyl-   i-Bu Isobutyl-   t-Bu tert-butyl-   Ph Phenyl-   Bn Benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz Carbobenzyloxy-   CH₂Cl₂ Dichloromethane-   CH₃CN or ACN Acetonitrile-   CDCl₃ deutero-chloroform-   CHCl3 Chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1.2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine

Hunig's base

-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH Ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    (phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex Hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH Methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ Ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl2 triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P® propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis.

IV. Biology In Vitro Assays

The effectiveness of compounds of the present invention as ROCKinhibitors can be determined in a 30 μL assay containing 20 mM HEPES, pH7.5, 20 mM MgCl₂, 0.015% Brij-35, 4 mM DTT, 5 μM ATP and 1.5 μM peptidesubstrate (FITC-AHA-AKRRRLSSLRA-OH). Compounds were dissolved in DMSO sothat the final concentration of DMSO was <2%, and the reaction wasinitiated with Rho kinase variants. After incubation, the reaction wasterminated by the addition of EDTA and the phosphorylated andnon-phosphorylated peptides separated using a LABCHIP® 3000 Reader(Caliper Life Sciences). Controls consisted of assays that did notcontain compound, and backgrounds consisted of assays that containedenzyme and substrate but had EDTA from the beginning of the reaction toinhibit kinase activity. Compounds were tested in dose-response format,and the inhibition of kinase activity was calculated at eachconcentration of compound. The inhibition data were fit using acurve-fitting program to determine the IC₅₀; i.e., the concentration ofcompound required to inhibit 50% of kinase activity.

Representative Examples were tested in the ROCK assay described aboveand found having ROCK inhibitory activity. Their ROCK inhibitoryactivity (IC₅₀ values) of ≤3 μM (3000 nM) was observed and shown inTable A below. The ranges of the ROCK IC₅₀ values are as follows:+(100.1-2100 nM)++(15.1-100 nM)+++(5.1-15 nM)++++(2.01-5 nM)+++++(0.2-2nM)

TABLE A Example No. ROCK2 Activity 1 + 2 + 3 + 4 + 5 ++++ 6 + 7 +++ 8 ++9 ++ 10 + 11 ++ 12 ++ 13 ++++ 14 ++++ 15 +++ 16 ++++ 17 + 18 + 19 + 20+++++ 21 ++++ 22 +++ 23 +++ 24 ++++ 25 +++ 26 ++++ 27 +++ 28 ++ 29 +++30 ++ 31 ++++ 32 ++++ 33 +++++ 34 ++ 35 +++ 36 ++++ 37 +++ 38 +++ 39 +++40 ++++ 41 ++++ 42 ++ 43 +++ 44 + 45 +++ 46 + 47 + 48 + 49 + 50 +++ 51+++ 52 ++ 53 ++++ 54 +++++ 55 +++ 56 +++ 57 +++ 58 ++++ 59 +++ 60 ++ 61++++ 62 +++++ 63 +++++ 64 +++ 65 ++++ 66 +++ 67 ++++ 68 ++++ 69 ++++ 70++++ 71 +++ 72 +++++ 73 ++++ 74 ++++ 75 ++ 76 ++++ 77 ++ 78 +++ 79 ++++80 +++++ 81 +++++ 82 ++++ 83 +++++ 84 +++ 85 ++++ 86 +++++ 87 +++++ 88+++++ 89 +++++ 90 +++++ 91 +++++ 92 +++++ 93 ++++ 94 +++ 95 +++ 96 ++ 97+++++ 98 ++++ 99 +++++ 100 + 101 ++ 102 +++ 103 ++ 104 + 105 +++++ 106 +107 +++++ 108 ++++ 109 ++++ 110 ++ 111 ++ 112 ++++ 113 ++++ 114 ++++ 115++++ 116 ++++ 117 ++ 118 ++ 119 +++++ 120 +++++ 121 +++++ 122 +++++ 123++++ 124 ++ 125 ++++ 126 +++++ 127 +++++ 128 ++++ 129 +++ 130 +++ 131+++++ 132 +++++ 133 +++++ 134 +++++ 135 +++++ 136 ++++ 137 ++++ 138+++++ 139 +++++ 140 +++++ 141 +++ 142 ++++ 143 ++++ 144 +++ 145 ++++ 146++++ 147 ++++ 148 +++ 149 +++ 150 ++++ 151 +++ 152 ++++ 153 ++++ 154++++ 155 ++++ 156 +++ 157 +++++ 158 ++++ 159 ++++ 160 +++++ 161 +++ 162++ 163 ++ 164 ++ 165 +++ 166 +++++ 167 +++++ 168 ++ 169 +++ 170 +++++171 ++++ 172 ++++ 173 +++++ 174 +++++ 175 ++ 176 +++ 177 +++++ 178 ++++179 +++++ 180 ++ 181 +++++ 182 ++++ 183 ++++ 184 +++++ 185 +++++ 186++++ 187 +++++ 188 +++++ 189 +++++ 190 +++++ 191 ++++ 192 ++++ 193 +++194 +++ 195 +++ 196 ++++ 197 +++++ 198 +++++ 199 ++++ 200 +++ 201 ++++202 +++ 203 +++ 204 +++++ 205 ++++ 206 +++++ 207 ++++ 208 ++++ 209 +++210 ++++ 211 ++++ 212 +++++ 213 +++ 214 ++++ 215 +++ 216 +++++ 217 +++++218 +++++ 219 +++++ 220 +++++ 221 +++++ 222 +++++ 223 +++++ 224 +++++225 +++++ 226 +++++ 227 ++ 228 +++ 229 +++ 230 ++ 231 ++ 232 +++ 233 +++234 ++++ 235 +++++ 236 +++++ 237 ++++ 238 ++++ 239 +++++ 240 ++++ 241++++ 242 ++++ 243 ++++ 244 +++ 245 +++ 246 ++++ 247 ++++ 248 +++ 249 +++250 +++ 251 +++ 252 +++ 253 +++ 254 +++ 256 ++ 257 ++ 258 +++ 259 +++260 +++ 261 ++ 262 + 263 +++ 264 ++ 265 + 266 + 267 + 268 +++++ 269+++++ 270 +++++ 271 ++++ 272 +++ 273 274 +++ 275 +++ 276 ++ 277 +++++278 +++ 279 ++++ 280 +++ 281 +++ 282 + 283 + 284 ++++ 285 ++ 286 ++ 287+++++ 288 ++ 289 ++ 290 ++++ 291 +++ 292 ++ 293 ++ 294 +++ 295 +++ 296 +297 ++++ 298 +++ 299 ++ 300 +++ 301 ++++ 302 +++++ 303 +++ 304 ++ 305 ++306 +++ 307 +++ 308 +++ 309 ++ 310 ++ 311 +++ 312 +++ 313 +++ 314 +++315 ++ 316 +++ 317 +++ 318 +++ 319 ++ 320 +++ 321 + 322 ++++ 323 + 325+++ 326 ++++ 327 ++++ 328 ++++ 329 +++++ 330 ++ 331 +++ 332 +++++ 333+++ 334 +++ 335 ++++ 336 ++ 337 +++ 338 ++ 339 ++ 340 +++ 341 ++ 342 +343 ++ 344 + 345 + 346 ++ 347 + 348 ++ 349 +++ 350 ++++ 351 + 352 ++ 353+++ 354 +++ 355 ++ 356 ++ 357 ++ 358 ++ 359 + 360 ++ 361 +++ 362 ++ 363++ 364 +++ 365 ++ 366 +++ 367 +++ 368 +++ 369 ++ 370 +++ 371 ++ 372 ++373 ++ 374 ++ 375 ++ 377 ++ 378 +++++ 379 +++ 380 +++ 381 ++++ 382 ++++383 +++++ 384 +++++ 385 +++++ 386 ++++ 387 ++++ 388 ++++ 389 +++ 390 +++391 +++++ 392 +++++ 393 +++++ 394 +++++ 395 ++++ 396 ++++ 397 +++++ 398+++++ 399 ++++ 400 +++++ 401 ++++ 402 + 403 ++++ 404 ++ 405 +++++ 406+++++ 407 ++ 408 ++++ 409 ++++ 410 ++++ 411 +++ 412 ++++ 413 +++++ 414+++++ 415 + 416 +++++ 417 +++++ 418 +++++ 419 ++++ 420 +++ 421 ++ 422++++ 423 ++++ 425 +++ 426 +++++ 427 +++ 428 +++ 429 ++ 430 +++ 431 +++++432 ++++ 433 ++++ 434 +++++ 435 +++ 436 +++++ 437 ++++ 438 + 439 +++++440 +++++ 441 +++++ 442 +++++ 443 +++++ 444 ++++ 445 ++ 446 ++++ 447++++ 448 ++++ 449 +++ 450 ++ 451 +++ 452 +++++ 453 ++ 454 ++ 455 ++++457 ++ 458 + 459 + 460 ++ 461 + 462 ++ 463 ++ 464 + 465 +++ 467 ++ 468 +469 ++ 470 +++++ 471 ++++

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation; the type and nature of theactive agent being formulated; the patient to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrvlamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of ROCK. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving ROCK. For example, a compound of the presentinvention could be used as a reference in an assay to compare its knownactivity to a compound with an unknown activity. This would ensure theexperimentor that the assay was being performed properly and provide abasis for comparison, especially if the test compound was a derivativeof the reference compound. When developing new assays or protocols,compounds according to the present invention could be used to test theireffectiveness.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically-acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat cardiovascular and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc, that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by methodsavailable to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35-37 (1981)). General synthetic schemesfor preparing compounds of the present invention are described below.These schemes are illustrative and are not meant to limit the possibletechniques one skilled in the art may use to prepare the compoundsdisclosed herein. Different methods to prepare the compounds of thepresent invention will be evident to those skilled in the art.Additionally, the various steps in the synthesis may be performed in analternate sequence in order to give the desired compound or compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al., (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Scheme 1 shows the synthesis of the generic compound 1f from the commonintermediate 1e via functionalization of the top linker portion L-H. Thefunctionalization of intermediate 1e includes, but is not limited toamide, carbamate and urea formations. Homer-Wadsworth-Emmons reactionbetween commercially available (or prepared via known literatureprocedures) bicyclic ketone 1a and commercially available (or preparedvia known literature procedures) phosphonate 1b under treatment withbases such as, but not limited to, Cs₂CO₃, KOtBu and LiHMDS, and insolvents such as iPrOH, tBuOH and THF gives rise to the alkene 1c. Thealkene 1c is treated with hydrazine or hydrazine hydrate in solvents,such as dioxane and THF, to afford the protected intermediate 1d.Cleavage of the protecting group, such as using TFA or HCl in dioxanewhen PG=Boc, affords the free linker intermediate 1e. Intermediate 1e isconverted to the target 1f by treatment with a functionalizing reagentsincluding, but not limited to an acid chloride, an isocyanate or acarbamic chloride, in the presence of a base such as pyridine or DIEA.In addition, intermediate 1e is derivatized with heteroaryl halide inthe presence of a base such as pyridine or DIEA and an optionalcatalysts such as Cu(I), Cu(II), Pd(0) and Pd(II) compounds, and anappropriate ligand such as L-proline, XantPhos and SPhos. Alternatively,target 1f is prepared by coupling of intermediate 1e with a carboxylicacid in the presence of a coupling reagent, such as HATU or BOP, and abase such as DIEA. Alternatively, when L-PG is an alkyl ester, removalof the protecting group via saponification, such as using LiOH inaqueous McOH, affords a free carboxylic acid intermediate 1e.Intermediate 1e can then be converted to the target 1f by coupling withan appropriate amine using a coupling agent such as HATU or BOP or viaheterocycle formation.

Scheme 2 depicts the synthesis of the generic compound 2f, beginningfrom bicyclic ketone 1a (either commercially available or prepared byliterature methods). The conversion of the ketone 1a to the respectivetosylhydrazone 2a is achieved by treatment with tosylhydrazine.Intermediate 2a is then coupled via Barluenga reaction (Nature Chem,2009, 1, 494) with boronic acid 2c, prepared via Suzuki-Miyauraborylation of commercially available (or prepared by literature methods)heterocyclic scaffold 2b. Removal of the protecting group, such as usingLiOH in aqueous MeOH when L-PG is an alkyl ester or by treatment withTFA or HCl when L-PG=N-Boc, affords the free linker intermediate 2e.Intermediate 2e is then converted to the target 2f by means described inScheme 1.

Scheme 3 shows a synthesis of phthalazinone targets 3f-i, beginning fromspiro[3,3]heptane intermediate 3a, which is either commerciallyavailable or can be prepared by literature methods. As outlined inScheme 1. Homer-Wadsworth-Emmons reaction with commercially available(or prepared according to known literature procedure) phosphonate 3b,and subsequent treatment of the respective alkene 3c with hydrazine orhydrazine hydrate affords protected intermediate 3d. An appropriatedeprotection method yields common intermediate 3e. Intermediate 3e isconverted to the urea target 3f by treatment with an isocyanate,carbamic chloride or 4-nitrophenyl carbamate. Intermediate 3e isconverted to the carbamate target 3g by treatment with a chloroformatein the presence of a base such as DIEA or TEA. Intermediate 3e isconverted to the amide target 3 h by treatment with an acid chloride inthe presence of a base such as pyridine or DIEA. Alternatively, target 3h is prepared by coupling of intermediate 3e with a carboxylic acid inthe presence of a coupling reagent, such as HATU or BOP, and a base suchas DIEA. Intermediate 3e is coupled with heteroaryl halide under thermalSNAr conditions in the presence of a base such as DIEA in a solvent suchas DMF or NMP to afford 3i. Alternatively, 3e and heteroaryl halide maybe coupled under Buchwald-Hartwig N-arylation conditions using a basesuch as Cs₂CO₃, a catalyst such as Pd₂(dba)₃ and an appropriate ligandto afford 3i.

Scheme 4 shows a synthesis of phthalazinone targets 4e-f, beginning fromspiro[3.3]heptane intermediate 4a, which is either commerciallyavailable or can be prepared by literature methods. Analogously to thepreviously described sequence in Scheme 3, common intermediate 4d isobtained. After activation with an appropriate reagent such as HATU, BOPor oxalyl chloride, the subsequent coupling with an amine gives rise toamides 4e. Alternatively, intermediate 4d may be converted toheterocyclic analog 4f, which include, but not limited to oxazoles,isoxazoles, imidazoles, triazoles, tetrazoles and oxadiazoles. Forinstance, conversion of acid 4d to the respective hydrazide, andsubsequent treatment with an acid chloride, and T3P® to affect ringclosure may lead to the oxadiazole 4f derivatives.

Scheme 5 starts with an acid intermediate 4d, which is subjected to ahomologation protocol, which may include, but not limited toAmdt-Eistert homologation or the reduction/trichloromethylation/NaBHsequence as described in Org. Lett, 2008, 10, 3853. The homologatedprecursor 5a is then converted to the target amides Sc or heterocycles5b as described in Scheme 4.

Scheme 6 reveals the preparation of isoquinolinone targets 6f-i,beginning from spiro[3.3]heptane intermediate 3a, which is eithercommercially available or can be prepared by literature methods. Asoutlined in Scheme 2, after preparation of the respective tosylhydrazone6b and boronic acid 6c according to known procedures, and subsequentBarluenga coupling (Nature Chem, 2009, 1, 494) allows for thepreparation of protected intermediate 6d. An appropriate deprotectionmethod, which may include but not limited to treatment with TFA or HClin dioxane when PG=Boc, gives rise to the common intermediate 6e.Intermediate 6e is then converted to the targets 6f-i using theapproaches outlined in Scheme 3.

Scheme 7 shows a synthesis of isoquinolinone targets 4e-f, beginningfrom spiro[3,3]heptane intermediate 4a, which is either commerciallyavailable or can be prepared by literature methods. Analogously to thepreviously described sequence in Scheme 6, common intermediate 7c isobtained. After activation with an appropriate reagent such as HATU, BOPor oxalyl chloride, the subsequent coupling with an amine providesaccess to amides 7d. Alternatively, intermediate 7c may be converted tothe heterocyclic analog 4e as described in Scheme 4.

Scheme 8 begins with an acid intermediate 7c, which is subjected to ahomologation protocol as described in Scheme 5. The homologatedprecursor 8a is then converted to the target amides 8c or heterocycles8b as described in Scheme 4.

Scheme 9 outlines the general pathway to access substitutedspiro[3,3]heptanes 9n-p, and constitutes a series of malonate additions,functionalizations and repeated malonate additions to build diverselyderivatized spiroheptane systems. The sequence begins with a coupling ofthe activated heterocycle 9a (either commercially available or preparedby a known procedure) and malonate under SNAr reaction conditions in thepresence of bases such as NaH, NaOtBu, LiHMDS and such, or optionallyunder copper-catalyzed conditions involving, but not limited to, CuI anda ligand such as L-proline, to afford the malonate 9b. Subsequenttreatment of 9b with an organometallic reagent such as organolithium,organomagnesium, organozinc or organoaluminum species where R¹═H, alkyl,aryl or heteroaryl can afford derivatives 9c. Repeated addition of theaforementioned organometallic species affords diol 9d. Organometallicspecies may be represented by hydride sources like LAH, NaBH₄ andsimilar reducing agents giving rise analogs where R¹, R², etc. ═H. Diol9d is then is activated with TsCl, MsCl, NsCl or similar reagents in thepresent of bases such as pyridine, TEA or DIEA to afford derivative 9e,which is further condensed with a malonate to yield the cyclobutane 9f.Repeating of the above sequence then gives rise to spiro[3,3]heptanemalonate analog 9j. Subsequent Krapcho decarboxylation in solvents suchas wet DMSO and optionally in the presence of salts like LiCl, andsubsequent hydrolysis provides analog 9m. Compound 9m is then converteddirectly, or after the respective Curtius rearrangement, to the targetderivatives 9n-p using the methods described in Schemes 1 to 8.

Scheme 10 shows routes to the substituted spiroheptanes, wherederivatization occurs either on the top cyclobutane ring in compound10e, or the bottom ring in 10i. Commercially available (or prepared viaknown procedure) diketone 10a is converted to the monoketal 10b, andsubsequently is functionalized using RX such as alkyl halides under thepresence of a base such as LiHMDS, LDA, etc, to provide substitutedanalog 10c. Reductive amination under appropriate conditions (such asamine/NaBH₄/methanol) affords analog 10d. Ensuing cleavage of the ketalgroup under acidic conditions such as TsOH or HCl unmasks ketone 10e.Alternatively, intermediate 10c may be reduced and protected at thealcohol portion of the molecule to give the compound 10f. After ketalcleavage and reductive amination described above compound 10h may beobtained. Finally, selective deprotection and oxidation of the acquiredalcohol provides target 10i. Both ketones 10e and 10i may be used inSchemes 3 and 6 as a starting materials to provide the respectivesubstituted spiro[3,3]heptane targets.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc or DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% H₂O, 10%/0MeOH, 0.1% TFA) and Solvent B (10% H₂O, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% H₂O, 10% ACN, 0.1% TFA) and SolventB (10% H₂O, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A(98% H₂O, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H₂O, 0.05% TFA,UV 220 nm) (or) SunFire Prep C18 OBD 5μ 30×100 mm, 25 min gradient from0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1 (or) WatersXBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Solvent A; water with 20-mM ammoniumacetate; Solvent B: 95:5 acetonitrile:water with 20-mM ammonium acetate;Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B:Flow: 20 mL/min.

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A: SunFire C18 column (3.5 μm C18, 3.0×150 mm). Gradient elution(1.0 mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent Bfor 5 min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA)and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method B: XBridge Phenyl column (3.5 μm C18, 3.0×150 mm). Gradientelution (1.0 mL/min) from 10-100% Solvent B over 10 min and then 100%Solvent B for 5 min was used. Solvent A is (95% water, 5% acetonitrile,0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV254 nm).

Method C: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A;5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 OC;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B: Flow: 1 mL/min.

Method D: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A;5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10 mM ammonium acetate; Temperature: 40° C.;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 0.5 mL/min.

Method E: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A;5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Temperature: 50 OC; Gradient: 0-100%B over 3 minutes: Flow: 1.11 mL/min.

Method F: Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A;5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 OC;Gradient: 0-100% B over 3 minutes; Flow: 1.11 mL/min.

Intermediate 1: 4-(6-Aminospiro[3.3]heptan-2-yl)phthalazin-1(2H)-one, 2TFA

Intermediate 1A: tert-butyl(6-(3-oxoisobenzoturan-1(3H)-ylidene)spiro[3.3]heptan-2-yl)carbamate

Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (0.591 g, 2.44mmol) (J. Med. Chem, 2008, 51, 6581) and tert-butyl(6-oxospiro[3.3]heptan-2-yl)carbamate (0.500 g, 2.22 mmol) weredissolved in anhydrous iPrOH (14.80 mL). Then, cesium carbonate (0.868g, 2.66 mmol) was added, and the reaction mixture was stirred at rt for16 h. A thick white suspension formed. The reaction mixture was dilutedwith DCM, CELITE® was added, and solvent was removed under reducedpressure and purified via flash chromatography (gradient from 0 to 50%ethyl acetate/hexanes) to give 0.740 g (98% yield) of Intermediate 1A asa white solid. MS(ESI) m/z: 342.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ7.89 (d, J=7.7 Hz, 1H), 7.86-7.76 (m, 1H), 7.67-7.54 (m, 2H), 7.12 (d,J=7.9 Hz, 1H), 3.96-3.81 (m, 1H), 3.25-3.18 (m, 1H), 3.09 (d, J=5.7 Hz,2H), 2.97 (d, J=1.3 Hz, 1H), 2.44-2.33 (m, 2H), 2.11-1.99 (m, 2H), 1.37(s, 9H).

Intermediate 1B: tert-butyl(6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 1A (0.740 g, 2.17 mmol) was placed in a pressure vial,thereafter dioxane (10 mL) and hydrazine hydrate (1.58 mL, 32.5 mmol)were added sequentially. The reaction mixture was stirred at rt for 15min, and then at 100° C. for 16 h. The reaction mixture was cooled to t,diluted with EtOAc (100 mL), washed with water (2×50 mL), brine (1×50mL), dried (Na₂SO₄) and concentrated. The residue was purified via flashchromatography (gradient from 20 to 100% ethyl acetate/hexanes) toafford 0.703 g (91% yield) of Intermediate 1B as a white solid. MS(ESI)m/z: 356.1 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.28-8.20(m, 1H), 7.93-7.86 (m, 1H), 7.85-7.76 (m, 2H), 7.04 (d, J=7.9 Hz, 1H),3.84 (quin, J=8.5 Hz, 2H), 2.47-2.40 (m, 1H), 2.33 (d, J=9.0 Hz, 1H),2.28 (d, J=8.6 Hz, 2H), 2.16-2.05 (m, 1H), 2.05-1.98 (m, 1H), 1.88-1.78(m, 1H), 1.36 (s, 9H).

Intermediate 1

Intermediate 1B (0.105 g, 0.295 mmol) was dissolved in neat TFA (3 mL),and the reaction mixture was stirred at rt for 15 min. TFA was removedunder reduced pressure, then the residue was co-evaporated with Et₂O(3×5 mL) and dried under vacuum to give 0.140 g (98% yield) ofIntermediate 1 as an off-white solid. MS(ESI) m/z: 256.1 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.25 (d J=7.7 Hz, 1H), 7.98-7.88 (m,3H), 7.87-7.78 (m, 2H), 3.68-3.51 (m, 1H), 2.62-2.51 (m, 3H), 2.42-2.29(m, 3H), 2.28-2.14 (m, 2H), 2.06 (dd, J=11.7, 8.6 Hz, 1H).

Intermediate 2:4-((aR)-6-Aminospiro[3.3]heptan-2-yl)phthalazin-1(2H)-one, TFA

Intermediate 3:4-((aS)-6-Aminospiro[3.3]heptan-2-yl)phthalazin-1(2H)-one, TFA

Intermediate 2A: tert-butyl((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamateIntermediate 3A: tert-butyl((aS)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 1B (0.100 g, 0.281 mmol) was separated on chiral SFC(Instrument; Berger Multigram II SFC: Column: CHIRALCEL® OJ, 21×250 mm,5μ; Mobile Phase; 15% Methanol/85% CO₂; Flow Conditions: 45 mL/min, 120Bar, 40° C.; Detector Wavelength: 220 nm). Collected 1st peak at 5.12min, concentrated to afford Intermediate 2A (0.046 g, 46% yield) as anoff-white solid. MS(ESI) m/z: 356.1 (M+H)⁺; ee>99%; ¹H NMR (400 MHz,DMSO-d₆) δ 12.40 (s, 1H), 8.29-8.20 (m, 1H), 7.93-7.86 (m, 1H),7.85-7.76 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 3.85 (quin, J=8.5 Hz, 2H),2.47-2.40 (m, 1H), 2.33 (d, J=9.0 Hz, 1H), 2.28 (d, J=8.6 Hz, 2H),2.15-2.05 (m, 1H), 2.05-1.98 (m, 1H), 1.88-1.78 (m, 1H), 1.36 (s, 9H).

Collected 2nd peak at 6.36 min, concentrated to afford Intermediate 3A(0.049 g, 49% yield) as an off-white solid. MS(ESI) m/z: 356.1 (M+H)⁺;ee=99%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.28-8.20 (m, 1H),7.92-7.87 (m, 1H), 7.85-7.76 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 3.83(quin, J=8.5 Hz, 2H), 2.47-2.40 (m, 1H), 2.33 (d, J=9.0 Hz, 1H), 2.28(d=8.6 Hz, 2H), 2.16-2.05 (m, 1H), 2.05-1.98 (m, 1H), 1.88-1.78 (m, 1H),1.35 (s, 9H).

Intermediate 2

Intermediate 2A (40 mg, 0.113 mmol) was dissolved in neat TFA (1.5 mL),and the reaction mixture was stirred at rt for 15 min. TFA was removedunder reduced pressure, then the residue was co-evaporated with Et₂O(5×10 mL) and dried under vacuum to give Intermediate 2 (41 mg, 99%yield) as an off-white solid. MS(ESI) m/z; 256.1 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 12.39 (s, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.99-7.88 (m,3H), 7.87-7.78 (m, 2H), 3.68-3.51 (m, 1H), 2.62-2.50 (m, 3H), 2.42-2.29(m, 3H), 2.28-2.14 (m, 2H), 2.06 (dd, J=11.7, 8.6 Hz, 1H).

Intermediate 3

Intermediate 3A (40 mg, 0.113 mmol) was dissolved in neat TFA (1.5 mL),and the reaction mixture was stirred at it for 15 min. TFA was removedunder reduced pressure, then the residue was co-evaporated with Et₂₀(5×10 mL) and dried under vacuum to give Intermediate 3 (41 mg, 99%yield) as an off-white solid. MS(ESI) m/z; 256.1 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 12.39 (s, 1H), 8.25 (d, J=7.7 Hz 1H), 7.99-7.88 (m, 3H),7.87-7.78 (m, 2H), 3.68-3.51 (m, 1H), 2.62-2.50 (m, 3H), 2.42-2.29 (m,3H), 2.28-2.14 (m, 2H), 2.06 (dd, J=11.7, 8.6 Hz, 1H).

Intermediate 4:6-(4-Oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptane-2-carboxylic acid

Intermediate 4A: Methyl6-(3-oxoisobenzofuran-1(3H)-ylidene)spiro[3.3]heptane-2-carboxylate

Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (1.584 g, 6.54mmol) (J. Med. Chem, 2008, 51, 6581) and methyl6-oxospiro[3.3]heptane-2-carboxylate (1.00 g, 5.95 mmol) were dissolvedin anhydrous iPrOH (39.6 mL). Then, cesium carbonate (2.13 g, 6.54 mmol)was added, and the reaction mixture was stirred at rt for 16 h. A thickwhite suspension formed. The reaction mixture was diluted with DCM,CELITE® was added, and solvent was removed under reduced pressure. Theresidue was purified via flash chromatography (gradient from 10 to 100%ethyl acetate/hexanes) to afford Intermediate 4A (1.61 g, 95% yield) asan amber syrup. MS(ESI) m/z: 285.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆)7.95-7.84 (m, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.52-7.40 (m, 2H), 3.70 (s,3H), 3.24-3.07 (m, 4H), 2.52-2.36 (m, 5H).

Intermediate 4B: Methyl6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptane-2-carboxylate

Intermediate 4A (1.61 g, 5.66 mmol) was placed in a pressure vial, anddioxane (15 mL) and hydrazine hydrate (0.824 mL, 17.0 mmol) were addedsequentially. The reaction mixture was stirred at rt for 15 min, andthen at 100° C. for 16 h. The reaction mixture was cooled to rt, dilutedwith EtOAc (250 mL), washed with water (2×100 mL), brine (1×50 mL),dried (Na₂SO₄) and concentrated. The residue was purified via flashchromatography (gradient from 1 to 15% MeOH/DCM) to afford Intermediate4B (1.185 g, 70% yield) as a white solid. MS(ESI) m/z: 299.1 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.31-8.18 (m, 1H), 7.95-7.86 (m,1H), 7.86-7.77 (m, 2H), 3.83 (quin, J=8.4 Hz, 1H), 3.59 (s, 3H), 3.05(quin, J=8.4 Hz, 1H), 2.48-2.41 (m, 2H), 2.40-2.22 (m, 4H), 2.11 (d,J=8.6 Hz, 2H).

Intermediate 4

Intermediate 4B (0.500 g, 1.68 mmol) was dissolved in THF (7.0 mL) andMeOH (1.397 mL), then LiOH (1 M in water) (5.03 mL, 5.03 mmol) wasadded. The reaction was heated to 50° C. for 2 h. The reaction mixturewas quenched with TFA (0.387 mL, 5.03 mmol) and concentrated underreduced pressure. The residue was purified by preparative HPLC to giveIntermediate 4 (0.261 g, 55% yield) as a white solid. MS(ESI) m/z: 285.0(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.24 (d, J=8.1 Hz,1H), 7.94-7.87 (m, 1H), 7.86-7.78 (m, 2H), 3.83 (quin, J=8.5 Hz, 1H),2.95 (quin, J=8.4 Hz, 1H), 2.47-2.36 (m, 2H), 2.36-2.32 (m, 2H),2.30-2.21 (m, 2H), 2.08 (d, J=8.4 Hz, 2H).

Intermediate 5:2-(6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)acetic acid

Intermediate 5A:4-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

Intermediate 4B (0.150 g, 0.503 mmol) was dissolved in anhydrous THF(7.5 mL), and the reaction mixture was stirred at 0° C. for 5 min. Then,LiBH₄ (0.027 g, 1.257 mmol) was added, and the reaction mixture wasstirred at 0° C. for additional 15 min. Then ice bath was removed, thereaction was allowed to reach rt and stir at this temperature for 1 h.Additional LiBH₄ (0.027 g, 1.257 mmol) was added, and the reactionmixture was stirred at rt for 16 h. The reaction mixture was carefullyquenched with NH₄Cl (aq.; ˜5 mL; CAUTION: hydrogen gas evolution), anddiluted with EtOAc (100 mL). The organic phase was washed with aq, NH₄Cl(25 mL) and brine (50 mL), dried (Na₂SO₄) and concentrated. The residuewas purified via flash chromatography (gradient from 1 to 15% MeOH/DCM)to afford Intermediate 5A (0.108 g, 79% yield) as a white solid. MS(ESI)m/z: 271.0 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.27-8.21(m, 1H), 7.94-7.87 (m, 1H), 7.86-7.78 (m, 2H), 4.40 (t J=5.3 Hz, 1H),3.83 (quin, J=8.5 Hz, 1H), 3.34 (t, J=5.6 Hz, 2H), 2.48-2.41 (m, 1H),2.38-2.16 (m, 5H), 1.95-1.84 (m, 2H), 1.66 (dd, J=11.3, 6.9 Hz, 1H).

Intermediate 5B:4-(6-(2,2,2-trichloro-1-hydroxyethyl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

To a solution of Intermediate 5A in anhydrous DMF (4.0 mL) was added DMP(0.203 g, 0.479 mmol) at 0° C. under Ar atmosphere. The cooling bath wasremoved, and the reaction mixture was stirred at rt for 12 h. Thereaction mixture was cooled to 0° C., then sodium trichloroacetate(0.244 g, 1.318 mmol) and trichloroacetic acid (0.215 g, 1.318 mmol)were added quickly. The reaction mixture was allowed to warm to rt andwas stirred at this temperature for 16 h. Additional sodiumtrichloroacetate (0.488 g, 2.636 mmol) and trichloroacetic acid (0.430g, 2.636 mmol) were added, and the reaction mixture was stirred at rtfor additional 3 h. The reaction mixture was quenched with aq. NaHCO₃(˜5 mL; CAUTION: carbon dioxide evolution), and the reaction mixture wasdiluted with EtOAc (100 mL) and water (50 mL). The organic phase wasseparated, washed with water (2×50 mL), dried (Na₂SO₄), andconcentrated. The residue was purified via flash chromatography(gradient from 1 to 10% MeOH/DCM) to afford Intermediate 5B (0.085 g,55% yield) as an off-white solid. MS(ESI) m/z: 386.9 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.00-7.77 (m,3H), 6.57 (dd, J=15.4, 6.8 Hz, 1H), 3.95-3.75 (m, 2H), 2.81-2.66 (m,1H), 2.60-2.53 (m, 1H), 2.41-2.24 (m, 4H), 2.24-2.05 (m, 1H), 2.00-1.78(m, 2H).

Intermediate 5

To a solution/suspension of Intermediate 5B (0.050 g, 0.129 mmol) intBuOH (3.0 mL), was added freshly powdered sodium hydroxide (0.017 g,0.426 mmol) at it under Ar atmosphere. The reaction mixture was stirredrapidly at rt for 10 min, then sodium borohydride (7.32 mg, 0.193 mmol)was added. The heterogeneous reaction mixture was warmed to 55° C., andstirred at this temperature for 16 h. Solvent was removed under reducedpressure, then the residue was dissolved in MeOH/DMF/TFA and purified bypreparative HPLC to afford Intermediate 5 (5.1 mg, 13% yield). MS(ESI)m/z: 299.1 (M+H)⁺; ¹H NMR (400 MHz, THF-d₈) δ 11.35 (br. s., 1H), 8.21(d, J=7.7 Hz, 1H), 7.72-7.62 (m, 2H), 7.62-7.54 (m, 1H), 3.68 (quin,J=8.4 Hz, 1H), 2.50-2.23 (m, 6H), 2.21 (d, J=7.7 Hz, 2H), 1.99 (ddd,J=11.5, 7.6, 4.2 Hz, 1H), 1.79 (dd, J=10.8, 8.1 Hz, 1H), 1.59-1.52 (m,1H).

Intermediate 6: 1-(2-Hydroxy-2-methylpropyl)-1H-indazole-3-carboxylicacid

Intermediate 6A: Ethyl1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (75 mg, 0.39 mmol)and 2,2-dimethyloxirane (0.088 mL, 0.99 mmol), was added acetonitrile(1.5 mL). To this mixture was added Cs₂CO₃ (193 mg, 0.591 mmol). Thevial was sealed and the mixture was stirred at 90° C. for 2.5 h. Thereaction mixture was partitioned between EtOAc and H₂O. The aqueousphase was extracted with EtOAc. The combined organic phase was washedwith brine, dried (Na₂SO₄) and concentrated. The crude product waspurified by flash chromatography (gradient from 0 to 100% ethylacetate/hexanes) to afford Intermediate 6A (45 mg, 43.5% yield) as acolorless oil. MS(ESI) m/z: 263.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d)δ 8.24 (dt, J=8.3, 0.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.43 (m, 1H),7.32 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.45 (s,2H), 2.73 (s, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.26 (s, 6H).

Intermediate 6

To a solution of Intermediate 6A (45 mg, 0.17 mmol) in THF (1 mL), wasadded IM aq. LiOH (0.20 mL, 0.20 mmol), followed by MeOH (0.3 mL). Thehomogeneous mixture was stirred at rt for 1.5 h. Additional 1M aq. LiOH(0.1 mL, 0.1 mmol) was added and the mixture was stirred at it for 14 h.The reaction mixture was partially evaporated to remove volatilesolvents. The solution was diluted with H₂O, then was acidified with 1 NHCl (˜0.3 mL). The aqueous phase was extracted with EtOAc (3×). Thecombined organic phase was washed with brine, dried (Na₂SO₄) andconcentrated to afford Intermediate 6 (40 mg, 100% yield) as anoff-white solid. MS(ESI) m/z: 235.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) 8.27 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.48 (t,J=7.6 Hz, 1H), 7.41-7.31 (m, 1H), 4.48 (s, 2H), 1.30 (s, 6H).

Intermediate 7: 1-(2,2-Difluoroethyl)-1H-pyrazole-5-carboxylic acid

Intermediate 8: 1-(2,2-Difluoroethyl)-1H-pyrazole-3-carboxylic acid

Intermediate 7A: Methyl 1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylateIntermediate 8A: Methyl 1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved indry MeCN (30 mL), then 2,2-difluoroethyl trifluoromethanesulfonate(0.633 mL, 4.76 mmol) was added, followed by cesium carbonate (1.94 g,5.95 mmol), and the reaction mixture was stirred at 60° C. for 2 h. Thereaction mixture was cooled to rt, diluted with EtOAc. Then CELITE® wasadded, and solvent was removed under reduced pressure. The residue waspurified by flash chromatography (solid loading on CELITE®): 0-60%EtOAc/Hex affording two products.

Intermediate 7A (0.271 g, 36% yield) as a colorless syrup: peak 1 elutedat ˜25% EtOAc. MS(ESI) m z: 190.9 (M+H)⁺; ¹H NMR: (400 MHz, CDCl₃) δ ppm7.57 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.31-5.95 (m, 1H), 4.98(td, J=13.1, 4.4 Hz, 2H), 3.91 (s, 3H); ¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm−122.87 (s, 2F).

Intermediate 8A: (0.398 g, 53% yield) as a colorless syrup: peak 2eluted at ˜45% EtOAc. MS(ESI) m/z: 190.9 (M+H)⁺; ¹H NMR: (400 MHz,CDCl₃) δ ppm 7.51 (d, J=2.4 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.29-5.94(m, 1H), 4.55 (td, J=13.4, 4.3 Hz, 2H), 3.94 (s, 3H); ¹⁹F-NMR: (376 MHz,CDCl₃) δ ppm −122.42 (s, 2F).

Intermediate 7

Intermediate 7A (0.398 g, 2.093 mmol) was dissolved in THF (8.7 mL) andMcOH (1.7 mL), then LiOH (1 M in water) (6.28 mL, 6.28 mmol) were added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.484 mL, 6.28 mmol), then concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative to afford Intermediate 7 (0.173 g, 46.9% yield) as awhite solid. MS(ESI) m/z: 176.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ13.59 (br. s., 1H), 7.64 (d, J=2.0 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H),6.60-6.12 (m, 1H), 4.98 (td, J=14.5, 4.0 Hz, 2H).

Intermediate 8

Intermediate 8A (0.271 g, 1.43 mmol) was dissolved in THF (5.9 mL) andMeOH (1.2 mL), then LiOH (1 M in water) (4.28 mL, 4.28 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.329 mL, 4.28 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 8 (0.177 g, 71% yield) as awhite solid. MS(ESI) m/z: 176.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ12.76 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.59-6.19(m, 1H), 4.72 (td, J=15.2, 3.7 Hz, 2H).

Intermediate 9: 1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylic acid

Intermediate 10: 1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylic acid

Intermediate 9A: Methyl1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate Intermediate 10A:Methyl 1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved indry MeCN (30 mL), then 3-bromo-1,1-trifluoropropane (0.507 mL, 4.76mmol) was added, followed by cesium carbonate (1.938 g, 5.95 mmol). Thereaction mixture was stirred at 60° C. for 2 h. Additional3-bromo-1,1,1-trifluoropropane (0.507 mL, 4.76 mmol) was added, followedby TBAI (0.146 g, 0.396 mmol), and the reaction mixture was stirred at60° C. for 14 h. Additional cesium carbonate (1.938 g, 5.95 mmol), TBAI(0.146 g, 0.396 mmol) and 3-bromo-1,1,1-trifluoropropane (0.507 mL, 4.76mmol) were added, and the reaction mixture was stirred at 60° C. for 6h. The reaction mixture was cooled to rt, diluted with EtOAc. ThenCELITE® was added, and solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (solid loading on CELITE®,0-55% EtOAc/Hex) affording two products.

Intermediate 9A (0.228 g, 26% yield) as a colorless syrup eluted at ˜20%EtOAc. MS(ESI) m/z: 222.9 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm 7.52(d, J=1.9 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 4.87-4.80 (m, 2H), 3.90 (s,3H), 2.78-2.66 (m, 2H); ¹⁹F-NMR; (471 MHz, CDCl₃) δ ppm −65.71 (s, 3F).

Intermediate 10A (0.257 g, 29% yield) as a colorless syrup eluted at˜40% EtOAc. MS(ESI) m/z: 222.9 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm7.45 (d, J=2.2 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 4.44 (t J=7.3 Hz, 2H),3.94 (s, 3H), 2.79 (qt, J=10.3, 7.2 Hz, 2H); ¹⁹F-NMR: (471 MHz, CDCl₃) δppm −65.66 (s, 3F).

Intermediate 9

Intermediate 9A (0.228 g, 1.026 mmol) was dissolved in THF (4.3 mL) andMcOH (0.9 mL), then LiOH (1 M in water) (3.08 mL, 3.08 mmol) was added.The reaction was heated to 50° C. for 16 h. The reaction mixture wasquenched with TFA (0.237 mL, 3.08 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 9 (0.115 g, 54% yield) as awhite solid. MS(ESI) m/z: 208.9 (M+H)⁺; ¹H NMR: (400 MHz, CDCl₃) δ ppm13.47 (br. s., 1H), 7.58 (d J=2.0 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 4.77(t, J=6.8 Hz, 2H), 2.83 (qt J=11.3, 6.8 Hz, 2H); ¹⁹F-NMR: (376 MHz,CDCl₃) δ ppm −64.15 (s, 3F).

Intermediate 10

Intermediate 10A (0.257 g, 1.157 mmol) was dissolved in THF (4.8 mL) andMeOH (1.0 mL), then LiOH (1 M in water) (3.47 mL, 3.47 mmol) was added.The reaction was heated to 50° C. for 16 h. The reaction mixture wasquenched with TFA (0.267 mL, 3.47 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to give Intermediate 10 (0.173 g, 72% yield) as awhite solid. MS(ESI) m/z: 208.9 (M+H)⁺; ¹H NMR: (400 MHz, CDCl₃) δ ppm12.67 (br. s., 1H), 7.90 (d, J=2.4 Hz, 1H), 6.69 (d J=2.2 Hz, 1H), 4.46(t, J=6.9 Hz, 2H), 2.91 (qt, J=11.2, 6.9 Hz, 2H); ¹⁹F-NMR: (376 MHz,CDCl₃) δ ppm −64.10 (s, 3F).

Intermediate 11: 1-(Cyclopropylmethyl)-1H-pyrazole-5-carboxylic acid

Intermediate 12: 1-(Cyclopropylmethyl)-1H-pyrazole-3-carboxylic acid

Intermediate 11A: Methyl 1-(cyclopropylmethyl)-1H-pyrazole-5-carboxylateIntermediate 12A: Methyl 1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved indry MeCN (30 mL), then (bromomethyl)cyclopropane (0.461 mL, 4.76 mmol)was added, followed by cesium carbonate (1.94 g, 5.95 mmol). Thereaction mixture was stirred at 60° C. for 2 h. The reaction mixture wascooled to it and diluted with EtOAc. Then CELITE® was added, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (solid loading on CELITE®, 0-55% EtOAc/Hex)affording two products.

Intermediate 11A (0.197 g, 28% yield) as a colorless syrup eluted at˜20% EtOAc. MS(ESI) m/z: 180.9 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm7.49 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 4.44 (d, J=7.2 Hz, 2H),3.88 (s, 3H), 1.44-1.31 (m, 1H), 0.57-0.48 (m, 2H), 0.45-0.37 (m, 2H).

Intermediate 12A (0.415 g, 58% yield) as a colorless syrup eluted at˜42% EtOAc. MS(ESI) m/z: 180.9 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm7.54 (d, J=2.5 Hz, 1H), 6.84 (d, J=2.5 Hz, 1H), 4.07 (d, J=7.2 Hz, 2H),3.93 (s, 3H), 1.32 (quint, J=7.6, 4.9 Hz, 1H), 0.71-0.64 (m, 2H),0.45-0.36 (m, 2H).

Intermediate 11

Intermediate 11A (0.197 g, 1.093 mmol) was dissolved in THF (4.6 mL) andMeOH (0.9 mL), then LiOH (1 M in water) (3.28 mL, 3.28 mmol) was added.The reaction was heated to 50° C. for 16 h. The reaction mixture wasquenched with TFA (0.25 mL, 3.3 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 11 (118 mg, 65% yield) as awhite solid. MS(ESI) m/z: 167.0 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm13.30 (s, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 4.36 (d,J=7.0 Hz, 2H), 1.32-1.19 (m, 1H), 0.50-0.41 (m, 2H), 0.37-0.30 (m, 2H).

Intermediate 12

Intermediate 12A (0.415 g, 2.30 mmol) was dissolved in THF (9.6 mL) andMeOH (1.92 mL), then LiOH (1 M in water) (6.91 mL, 6.91 mmol) was added.The reaction was heated to 50° C. for 16 h. The reaction mixture wasquenched with TFA (0.532 mL, 6.91 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 12 (270 mg, 71% yield) as awhite solid. MS(ESI) m/z: 167.0 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm12.55 (br. s., 1H), 7.85 (d, J=2.2 Hz, 1H), 6.68 (d J=2.2 Hz, 1H), 4.03(d, J=7.3 Hz, 2H), 1.38-1.15 (m, 1H), 0.62-0.47 (m, 2H), 0.44-0.30 (m,2H).

Intermediate 13: 1-cyclopropyl-1H-pyrazole-4-carboxylic acid

Intermediate 13A: Ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate

Ethyl 1H-pyrazole-4-carboxylate (0.500 g, 3.57 mmol) was dissolved inDCE (25 mL), then cyclopropylboronic acid (0.613 g, 7.14 mmol) andsodium carbonate (0.756 g, 7.14 mmol) were added. The reaction mixturewas heated to 70° C., and then a mixture of 2,2′-bipyridine (0.557 g,3.57 mmol) and copper(II) acetate (0.648 g, 3.57 mmol) were added to thereaction mixture in one batch. The reaction mixture was stirred at 70°C. under oxygen atmosphere (1 atm) for 24 h. Saturated aq. NaHCO₃solution was added to the reaction mixture, and it was extracted withEtOAc (3×). The organic phase was combined, and the solvent was removedunder reduced pressure. The residue was purified via flashchromatography (gradient from 0 to 65% ethyl acetate/hexanes) to affordIntermediate 13A (0.460 g, 72% yield) as a colorless syrup. MS(ESI) m/z:181.0 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm 7.93 (s, 1H), 7.87 (s, 1H),4.28 (q, J=7.0 Hz, 2H), 3.62 (tt, J=7.4, 3.9 Hz, 1H), 1.34 (t J=7.2 Hz,3H), 1.18-1.11 (m, 2H), 1.10-1.00 (m, 2H).

Intermediate 13

Intermediate 13A (0.460 g, 2.77 mmol) was dissolved in THF (11.5 mL) andMeOH (2.3 mL), then LiOH (1 M in water) (8.30 mL, 8.30 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.64 mL, 8.3 mmol), and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to give Intermediate 13 (0.307 g, 73% yield) as awhite solid. MS(ESI) m/z: 152.9 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δ ppm12.28 (br. s., 1H), 8.27 (s, 1H), 7.76 (s, 1H), 3.79 (tt, J=7.4, 3.8 Hz,1H), 1.13-1.05 (m, 2H), 1.02-0.88 (m, 2H).

Intermediate 14: 5-(Difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylicacid

Intermediate 14A: Methyl5-(difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylate

Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (J. Med. Chem.,54:8174 (2011)) (0.35 g, 2.24 mmol), K₂CO₃ (0.62 g, 4.48 mmol), andsodium chlorodifluoroacetate (0.684 g, 4.48 mmol) were dissolved in DMF(10 mL) and water (1 mL). The reaction was heated to 130° C. for 20 min.The reaction was diluted with water (100 mL) and EtOAc (200 mL). Theorganic phase was separated, washed with water (5×) and brine, dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (0-80% EtOAc/Hex gradient) to give Intermediate 14A(0.373 g, 81% yield) as a colorless syrup. MS(ESI) m/z: 207.0 (M+H)⁺; ¹HNMR: (400 MHz, CDCl₃) δ ppm 6.44 (t, J=1.0 Hz, 1H), 6.46 (t, J−72.2 Hz,1H), 3.92 (s, 3H), 3.82 (s, 3H); ¹⁹F-NMR; (376 MHz, CDCl₃) δ ppm −84.02(s, 2F).

Intermediate 14: 5-(Difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylicacid

Intermediate 14A (0.373 g, 1.81 mmol) was dissolved in THF (7.5 mL) andMeOH (1.5 mL), then LiOH (1 M in water) (5.43 mL, 5.43 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.42 mL, 5.4 mmol), and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 14 (0.230 g, 66% yield) as awhite solid. MS(ESI) m/z: 192.9 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm7.30 (t, J=70.4 Hz, 1H), 6.42 (s, 1H), 3.74 (s, 3H); ¹⁹F-NMR: (376 MHz,DMSO-d₆) δ ppm −84.72 (s, 2F).

Intermediate 15: 1-(Cyclopropyl)-1H-pyrazole-5-carboxylic acid

Intermediate 16: 1-(Cyclopropyl)-1H-pyrazole-3-carboxylic acid

Intermediate 15A: Methyl 1-(cyclopropyl)-1H-pyrazole-5-carboxylateIntermediate 16A: Methyl 1-(cyclopropyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol), was dissolved inDCE (25 mL), then cyclopropylboronic acid (0.681 g, 7.93 mmol) andsodium carbonate (0.840 g, 7.93 mmol) were added. The reaction mixturewas heated to 70° C., and then a mixture of 2,2′-bipyridine (0.619 g,3.96 mmol) and copper(II) acetate (0.720 g, 3.96 mmol) were added in onebatch. The reaction mixture was stirred at 70° C. under oxygenatmosphere (1 atm) for 2 d. Saturated aq. NaHCO₃ solution was added tothe reaction mixture, and it was extracted with EtOAc (3×). The combinedorganic phase was concentrated. The residue was purified by flashchromatography (solid loading on CELITE®, 0-65% EtOAc/Hex) affording twoproducts.

Intermediate 15A (0.119 g, 18% yield) as a colorless syrup eluted at˜20% EtOAc. MS(ESI) m/z: 167.0 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm7.40 (d, J=2.0 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 4.31-4.24 (m, 1H), 2.11(s, 3H), 1.29-1.22 (m, 2H), 1.10-1.00 (m, 2H).

Intermediate 16A (0.371 g, 56% yield) as a colorless syrup eluted at˜45% EtOAc. MS(ESI) m/z: 167.0 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm77.46 (d, J=2.4 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 3.92 (s, 3H), 3.67 (tt,J=7.4, 3.9 Hz, 1H), 1.23-1.15 (m, 2H), 1.09-1.01 (m, 2H).

Intermediate 15

Intermediate 15A (0.119 g, 0.716 mmol) was dissolved in THF (3 mL) andMeOH (0.6 mL), then LiOH (1 M in water) (2.15 mL, 2.15 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.166 mL, 2.15 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to give Intermediate 15 (0.064 g, 59% yield) as awhite solid. MS(ESI) m/z: 152.9 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm13.31 (br. s., 1H), 7.45 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 4.40(tt, J=7.5, 3.9 Hz, 1H), 1.16-1.08 (m, 2H), 1.03-0.93 (m, 2H).

Intermediate 16

Intermediate 16A (0.371 g, 2.23 mmol) was dissolved in THF (9.3 mL) andMeOH (1.9 mL), then LiOH (1 M in water) (6.7 mL, 6.7 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.516 mL, 6.70 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 16 (0.215 g, 63% yield) as awhite solid. MS(ESI) m/z: 152.9 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm12.59 (br. s., 1H), 7.87 (d, J=2.2 Hz, 1H), 6.65 (d, J=2.2 Hz, 1H), 3.82(tt, J=7.5, 3.8 Hz, 1H), 1.11-1.05 (m, 2H), 1.03-0.94 (m, 2H).

Intermediate 17: 1-(2-Hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylicacid

Intermediate 17A: Ethyl1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved indry MeCN (12 mL), then 2,2-dimethyloxirane (0.531 mL, 5.95 mmol) wasadded, followed by cesium carbonate (1.94 g, 5.95 mmol). The reactionmixture was stirred at 150° C. under microwave irradiation for 30 min.The reaction mixture was cooled to rt, diluted with EtOAc(transesterification occurred upon EtOAc addition). The residue waspurified by flash chromatography (solid loading on CELITE®, 20-100%EtOAc/Hex) affording Intermediate 17A (0.305 g, 36% yield) as acolorless syrup. MS(ESI) m/z: 213.0 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δppm 7.50 (d, J=2.4 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 4.40 (q, J=7.0 Hz,2H), 4.17 (s, 2H), 2.77 (s, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.20 (s, 6H).

Intermediate 17

Intermediate 17A (0.305 g, 1.44 mmol) was dissolved in THF (6 mL) andMeOH (1.2 mL), then LiOH (1 M in water) (4.31 mL, 4.31 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.332 mL, 4.31 mmol), and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to give Intermediate 17 (0.239 g, 90% yield) as acolorless syrup, which solidified upon standing. MS(ESI) m/z; 184.9(M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm 7.73 (d, J=2.2 Hz, 1H), 6.67(d, J=2.4 Hz, 1H), 4.08 (s, 2H), 1.06 (s, 6H).

Intermediate 18:6-Fluoro-1-(2-methylprop-1-en-1-yl)-1H-indazole-3-carboxylic acid

Intermediate 19:6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid

To a vial containing methyl 6-fluoro-1H-indazole-3-carboxylate (200 mg,1.03 mmol) in DMF (3 mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15mmol) and Cs₂CO₃ (403 mg, 1.236 mmol). The vial was sealed and themixture was stirred at 80° C. for 3 h. The mixture was quenched withwater, acidified with 1 N HCl and extracted with EtOAc. The organiclayer was concentrated and purified by flash chromatography (eluted withMeOH/DCM). Collected two fractions: 1st fraction: 5% MeOH; 2nd fraction:8% MeOH.

1st fraction afforded Intermediate 18 (26 mg, 11%). MS(ESI) 235.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 13.78 (br. s., 1H), 8.05 (dd, J=9.1,5.5 Hz, 1H), 7.55 (dt, J=9.9, 1.1 Hz, 1H), 7.44-7.32 (m, 1H), 7.21 (td,J=9.3, 2.3 Hz, 1H), 1.93 (d, J=1.1 Hz, 3H), 1.79 (d, J=1.4 Hz, 3H).

2nd fraction afforded Intermediate 19 (90 mg, 36%). MS(ESI) 253.1(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) d 8.10 (dd, J=9.0, 5.3 Hz, 1H),7.44 (dd, J=9.5, 2.0 Hz, 1H), 7.08 (td, J=9.1, 2.1 Hz, 1H), 4.39 (s,2H), 1.24 (s, 6H).

Intermediate 20: 1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazole-4-carboxylicacid

Intermediate 21: 1-(2,2-Difluoroethyl)-5-methyl-1H-pyrazole-4-carboxylicacid

Intermediate 20A: Ethyl1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-4-carboxylate Intermediate21A: Ethyl 1-(2,2-difluoroethyl)-5-methyl-1H-pyrazole-4-carboxylate

Ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.300 g, 1.95 mmol) wasdissolved in dry MeCN (15 mL), then 2,2-difluoroethyltrifluoromethanesulfonate (0.311 mL, 2.34 mmol) was added, followed bycesium carbonate (0.951 g, 2.92 mmol) and the reaction mixture wasstirred at 60° C. for 2 h. The reaction mixture was cooled to it anddiluted with EtOAc. Then CELITE® was added, and the solvent was removedunder reduced pressure. The residue was purified by flash chromatographyand was further purified by chiral SFC to afford two products.

Intermediate 20A (0.056 g, 13% yield) as a colorless oil, whichsolidified upon standing. MS(ESI) 219.0 (M+H)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.89 (s, 1H), 6.29-5.90 (m, 1H), 4.38 (td, J=13.4, 4.4Hz, 2H), 4.28 (q, J=7.0 Hz, 2H), 2.46 (s, 3H), 1.34 (t, J=7.2 Hz, 3H);¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm −122.64 (s, 2F).

Intermediate 21A (0.032 g, 7% yield) as a colorless oil. MS(ESI) 219.0(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.90 (s, 1H), 6.29-5.91 (m, 1H),4.41 (td, J=13.2, 4.4 Hz, 2H), 4.30 (q, J=7.1 Hz, 21-), 2.58 (s, 3H),1.35 (t, J=7.2 Hz, 3H); ¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm −122.36 (s, 2F).

Intermediate 20

Intermediate 20A (0.056 g, 0.257 mmol) was dissolved in THF (2.6 mL) andMeOH (2.6 mL), then LiOH (1 M in water) (0.77 mL, 0.77 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.059 mL, 0.77 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 20 (31.5 mg, 64% yield) as awhite solid. MS(ESI) 190.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.25(s, 1H), 8.19 (s, 1H), 6.56-6.12 (m, 1H), 4.57 (td J=15.0, 3.7 Hz, 2H),2.32 (s, 3H); ¹⁹F-NMR: (376 MHz, DMSO-d₆) δ ppm −122.94 (s, 2F).

Intermediate 21

Intermediate 21A (0.032 g, 0.147 mmol) was dissolved in THF (1.5 mL) andMeOH (1.5 mL), then LiOH (1 M in water) (0.44 mL, 0.44 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.034 mL, 0.440 mmol) and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC to afford Intermediate 21 (19.2 mg, 69% yield) as awhite solid. MS(ESI) 190.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.32(br. s., 1H), 7.80 (s, 1H), 6.58-6.19 (m, 1H), 4.62 (td, J=15.2, 3.7 Hz,2H), 2.51 (br. s., 3H); ¹⁹F-NMR: (376 MHz, DMSO-d₆) δ ppm −122.32 (s,2F).

Intermediate 22:2-bromo-4-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)thiazole-5-carboxamide

Intermediate 22. TFA (128 mg, 0.347 mmol) and2-bromo-4-methylthiazole-5-carboxylic acid (77 mg, 0.347 mmol) weredissolved in anhydrous DMF (5 mL). Then, isobutyl1,2-dihydro-2-isobutoxy-1-quinoline-carboxylate (0.103 mL, 0.347 mmol)was added, and the reaction mixture was stirred at 60° C. for 2 h.Additional 2-bromo-4-methylthiazole-5-carboxylic acid (77 mg, 0.35 mmol)and isobutyl 1,2-dihydro-2-isobutoxy-1-quinoline-carboxylate (0.103 mL,0.347 mmol) were added, and the reaction mixture was stirred at 60° C.for 16 h. The reaction mixture was cooled to rt and quenched with MeOH(1 mL). The reaction mixture was diluted with DMSO/MeOH/TFA and purifiedby preparative HPLC to afford Intermediate 22 (30 mg, 19% yield) as awhite solid. MS(ESI) 458.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.45(s, 1H), 8.47 (d, J=7.3 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.96-7.79 (m,3H), 4.31-4.17 (m, 1H), 3.97-3.83 (m, 1H), 2.66-2.55 (m, 1H), 2.52 (s,3H), 2.43-2.30 (m, 4H), 2.27-2.14 (m, 2H), 2.09-1.97 (m, 1H).

Intermediate 23:(R)-2-(3-fluoropyrrolidin-1-yl)-5-methylthiazole-4-carboxylic acid, TFA

Methyl 2-bromo-5-methylthiazole-4-carboxylate (188 mg, 0.796 mmol) and(R)-3-fluoropyrrolidine, HCl (250 mg, 1.99 mmol) were placed in apressure vial. Then NMP (3.0 mL) and DIEA (0.695 mL, 3.98 mmol) wereadded. The pressure vial was capped, and the reaction mixture wasstirred at 130° C. for 4 h. The reaction mixture was stirred at 130° C.for additional 14 h. The reaction mixture was diluted with EtOAc (100mL), washed with water (3×50 mL), brine (1×50 mL), and dried (Na₂SO₄).Solvent was removed under reduced pressure, the residue was dissolved inMeOH (7.5 mL), and LiOH (1 M aq.) (2.39 mL, 2.39 mmol) was added. Thereaction mixture was stirred at 50° C. for 1 h. The reaction mixture wasacidified with TFA (0.184 mL, 2.39 mmol), the solvent was removed underreduced pressure, and the residue was purified by preparative HPLC toafford Intermediate 23 (80 mg, 29% yield) as white hydroscopic solid.MS(ESI) m/z; 231.0 (M+H)⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ ppm 5.54-5.35(m, 1H), 3.69 (s, 1H), 3.64-3.59 (m, 1H), 3.59-3.52 (m, 1H), 3.50-3.39(m, 1H), 2.53 (s, 3H), 2.34-2.11 (m, 2H).

Intermediate 24:2-bromo-5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)thiazole-4-carboxamide

2-Bromo-5-methylthiazole-4-carboxylic acid (118 mg, 0.532 mmol) wassuspended in anhydrous DCM (5 mL), and a drop a DMF was added. Then,oxalyl chloride (2 M in DCM) (0.725 mL, 1.45 mmol) was added dropwise,and the reaction mixture was stirred for 1 h at rt (bubbling observed;the mixture became homogeneous). Then, DCM was removed under reducedpressure, and the obtained acid chloride (brown syrup) was used in thesubsequent step. In a separate flask, to a suspension of Intermediate 2,HCl (141 mg, 0.483 mmol) in THF (5 mL), was added DIEA (0.084 mL, 0.483mmol) and trimethylsilyl cyanide (0.644 mL, 4.83 mmol). The resultantsolution was stirred at rt for 10 min, and then was treated with asolution of acid chloride obtained as described above in THF (5 mL). Themixture was stirred at 50° C. for 1.5 h. The reaction mixture wasconcentrated, then trifluoroethanol (10 mL) was added. The residue waspurified by flash chromatography (solid loading on CELITE®, 0-100%EtOAc/Hex) affording Intermediate 24 (86 mg, 39%0/yield) as a off-whitesolid. MS(ESI) m/z: 459.0 (M+H)⁺; ¹H NMR: (400 MHz, CDCl₃) δ ppm 9.91(s, 1H), 8.46 (dd, J=7.8, 1.0 Hz, 1H), 7.86-7.80 (m, 1H), 7.80-7.74 (m,1H), 7.70 (d, J=8.1 Hz, 1H), 7.37 (br d, J=7.9 Hz, 1H), 4.47 (sxt, J=8.2Hz, 1H), 3.83 (quin, J=8.5 Hz, 1H), 2.77-2.69 (m, 1H), 2.63-2.34 (m,5H), 2.17 (dd, J=10.8, 8.8 Hz, 1H), 2.04-1.97 (m, 1H), 1.60 (s, 3H).

Intermediates 25-28 was prepared in a manner similar to Intermediate 17preparation, starting from the respective heterocyclic derivatives(indazole, indole, azaindazole, etc.).

Intermediate 25:1-(2-hydroxy-2-methylpropyl)-5-methoxy-1H-indazole-3-carboxylic acid

MS(ESI) m/z: 265.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.64 (d,J=9.2 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.11 (dd, J=9.2, 2.4 Hz, 1H),4.43 (s, 2H), 3.88 (s, 3H), 1.25 (s, 6H).

Intermediate 26:1-(2-hydroxy-2-methylpropyl)-6-methoxy-1H-indazole-3-carboxylic acid

MS(ESI) m z: 265 (M+H)⁺; ¹H HMR (400 MHz, methanol-d₄) δ ppm 7.93 (d,J=9.0 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.9, 2.1 Hz, 1H),4.36 (s, 2H), 3.86 (s, 3H), 1.22 (s, 6H)

Intermediate 27:5-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid

MS(ESI) m/z: 253.1 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ ppm 7.77-7.68(m, 2H), 7.32-7.20 (m, 1H), 4.43 (s, 2H), 1.30-1.21 (m, 6H)

Intermediate 28:1-(2-hydroxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

MS(ESI) m/z: 235.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.47 (dd,J=7.9, 1.5 Hz, 1H), 8.29 (d, J-=4.0 Hz, 1H), 8.14 (s, 1H), 7.23 (dd,J=7.9, 4.8 Hz, 1H), 4.33 (s, 2H), 1.17 (s, 6H)

Intermediate 29:6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.250 g, 1.21mmol) was suspended in MeCN (10 mL), then 2,2-dimethyloxirane (1.62 mL,18.2 mmol), K₂CO₃ (0.67 g, 4.85 mmol) and water (0.667 mL) were added.The reaction mixture was stirred under microwave irradiation at 120° C.for 30 min. The reaction mixture was concentrated under reducedpressure, the residue was dissolved in MeOH (4.5 mL)/THF (4.5 mL), andLiOH (1 M aq.) (3.64 mL, 3.64 mmol) was added. The reaction mixture wasstirred under microwave irradiation at 120° C. for 15 min. Solvent wasremoved under reduced pressure, and the residue was purified bypreparative HPLC to afford Intermediate 29 (0.185 g, 61% yield) as awhite solid. MS(ESI) m/z: 251.0. (M+H)⁺; ¹H NMR (500 MHz. DMSO-d₆) δ ppm8.55 (d, J=1.7 Hz, 1H), 8.28 (s, 1H), 7.96 (d, J=9.4 Hz, 1H), 7.38 (dd,J=9.6, 2.2 Hz, 1H), 3.82 (s, 2H), 1.22 (s, 6H).

Intermediates outlined below and pertaining to Table 6 (Intermediate30-31, and so on) were described in PCT Int. Appl. (2014), WO 2014113620A2 20140724.

Intermediate 30:6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

MS(ESI) m/z: 292.3. (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.38(dd, J=2.2, 0.7 Hz, 1H), 8.32 (s, 1H), 8.09 (dd, J=9.7, 0.7 Hz, 1H),7.36 (dd, J=9.7, 2.2 Hz, 1H), 4.51-4.43 (m, 2H), 3.97 (br. s., 4H),3.72-3.64 (m, 2H), 3.61-3.35 (m, 4H).

Intermediate 31: 2-morpholinothiazole-5-carboxylic acid

MS(ESI) m/z: 215.0. (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.82 (s,1H), 3.82-3.74 (m, 4H), 3.56-3.49 (m, 4H).

Intermediate 32: 6-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

Methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.392mmol), palladium(II) acetate (5.3 mg, 0.024 mmol), BINAP (0.022 g, 0.035mmol) and cesium carbonate (0.192 g, 0.588 mmol) were placed in apressure vial. The reaction mixture was degassed (3× vacuum/Ar), thenToluene (2 mL) and morpholine (0.044 mL, 0.510 mmol) were added. Thereaction mixture was degassed again, and stirred at 160° C. undermicrowave irradiation for 30 min. Additional amount of palladium(II)acetate (5.3 mg, 0.024 mmol). BINAP (0.022 g, 0.035 mmol) and morpholine(0.044 mL, 0.51 mmol) was added, and the reaction mixture was stirredfor additional 30 min at 160° C. Solvent was removed under reducedpressure. The obtained residue was dissolved in MeOH (2.0 mL)/THF (2.0mL), and LiOH (1 M aq.) (1.18 mL, 1.18 mmol) was added. The reactionmixture was stirred under microwave irradiation at 120° C. for 15 min.The mixture was acidified with TFA, the solvent was removed underreduced pressure, the residue was purified by preparative HPLC to giveIntermediate 32 (0.023 g, 24% yield) as an off-white solid. MS(ESI) m/z:248.0. (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.29 (br s, 1H),8.27-8.20 (m, 2H), 7.92 (d, J=9.4 Hz, 1H), 7.58 (dd, d=9.6, 2.2 Hz, 1H),3.81-3.73 (m, 4H), 3.17-3.07 (m, 4H).

Intermediate 33: 6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 33A: ethyl6-(difluoromethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.485mmol), K₂CO₃ (0.134 g, 0.970 mmol), and sodium chlorodifluoroacetate(0.148 g, 0.97 mmol) were dissolved in DMF (2.2 mL) and water (0.22 mL).The reaction was heated to 130° C. for 20 min (CAUTION: gas evolutionobserved, use open system). Reaction diluted with water (50 mL) andEtOAc (100 mL). Organic phase was separated, washed with water (3×25mL), brine (1×25 mL) and dried (Na₂SO₄). EtOAc was removed under reducedpressure and the residue was purified by flash chromatography (solidloading on CELITE®, 0-40% EtOAc/Hex) affording Intermediate 33A (74 mg,60% yield) as a white solid. MS(ESI) m/z: 257.0. (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.03 (d, J=1.7 Hz, 1H), 8.49 (s, 1H), 8.11 (dd,J=9.6, 0.8 Hz, 1H), 7.61 (dd, J=9.6, 1.9 Hz, 1H), 7.30 (t, J=73.3 Hz,1H), 4.31 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H); ¹⁹F-NMR: (471 MHz,DMSO-d₆) δ ppm −82.68 (s, 2F).

Intermediate 33

Intermediate 33A (0.050 g, 0.195 mmol) was dissolved in MeOH (1.5mL)/THF (1.5 mL), and LiOH (1 M aq.) (0.585 mL, 0.585 mmol) was added.The reaction mixture was stirred under microwave irradiation at 150° C.for 15 min. Solvent was removed under reduced pressure, the residue waspurified by preparative HPLC to afford Intermediate 33 (0.035 g, 79%yield) as a white solid. MS(ESI) m/z: 257.0 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.99 (s, 1H), 8.43 (s, 1H), 8.11 (d, J=9.6 Hz, 1H), 7.56(dd, J=9.5, 2.1 Hz, 1H), 7.28 (t, J=73.2 Hz, 1H); 19F-NMR: (471 MHz,DMSO-d₆) δ ppm −82.58 (s, 2F).

Intermediate 34:6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.080 g, 0.388mmol) was suspended in MeCN (3.0 mL), then 2,2-difluoroethyltrifluoromethanesulfonate (0.062 mL, 0.466 mmol) and cesium carbonate(0.379 g, 1.16 mmol) were added. The reaction mixture was stirred undermicrowave irradiation at 120° C. for 15 min. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in MeOH(1.5 mL)/THF (1.5 mL), and LiOH (1 M aq.) (1.94 mL, 1.94 mmol) wasadded. The reaction mixture was stirred under microwave irradiation at120° C. for 15 min. The reaction mixture was acidified with TFA, DMF wasadded, and the obtained solution was purified by preparative HPLC toafford Intermediate 34 (0.064 g, 68% yield) as a white solid. MS(ESI)m/z: 243.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.41 (s, 1H), 8.72(d, J=1.7 Hz, 1H), 8.32 (s, 1H), 7.99 (d, J=10.2 Hz, 1H), 7.43 (dd,J=9.6, 2.5 Hz, 1H), 6.45 (tt, J=54.3, 3.5 Hz, 1H), 4.44 (td, J=14.6, 3.4Hz, 2H); ¹⁹F-NMR: (471 MHz, DMSO-δ₆) δ ppm −125.92 (s, 2F).

Intermediate 35:6-(2-(1H-pyrazol-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.025 g, 0.121mmol) was dissolved in MeCN (1.00 mL)/THF (1,000 mL), then1-(2-bromoethyl)-1H-pyrazole (0.023 g, 0.133 mmol) and cesium carbonate(0.079 g, 0.242 mmol) were added. The reaction mixture was stirred undermicrowave irradiation at 120° C. for 15 min. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in MeOH(1 mL)/THF (1 mL), and LiOH (1 M aq.) (0.364 mL, 0.364 mmol) was added.The reaction mixture was stirred under microwave irradiation at 120° C.for 15 min. The reaction mixture was acidified with TFA, DMF was added,and the obtained solution was purified by preparative HPLC to affordIntermediate 35 (0.018 g, 55% yield) as a light-brown solid. MS(ESI)m/z: 272.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.59 (d, J=1.7 Hz,1H), 8.29 (s, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.47(d, J=1.4 Hz, 1H), 7.29 (dd, J=9.6, 2.2 Hz, 1H), 6.25 (t, J=2.1 Hz, 1H),4.55-4.49 (m, 2H), 4.46-4.41 (m, 2H).

Intermediate 36:6-(4,4-difluoropiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 36 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 282.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-δ₆) δ ppm 12.30 (s, 1H), 8.35(d, J=1.7 Hz, 1H), 8.26 (s, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.61 (dd,J=9.8, 2.1 Hz, 1H), 3.33 (br s, 4H), 2.18-2.06 (m, 4H); ¹⁹F-NMR (471MHz, DMSO-d₆) δ ppm −95.96 (br s, 2F).

Intermediate 37:6-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 37 was prepared by following a similar procedure to thatdescribed for Intermediate 35 employing the appropriate alkylhalide/triflate. MS(ESI) m/z: 276.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 9.96 (br s, 1H), 8.78 (d, J=1.7 Hz, 1H), 8.40 (s, 1H), 8.08 (d,J=9.6 Hz, 1H), 7.48 (dd, J=9.6, 2.2 Hz, 1H), 4.50-4.45 (m, 2H), 3.71 (brd, J=4.1 Hz, 2H), 2.16-2.03 (m, 4H), 2.00-1.88 (m, 4H).

Intermediate 38: 5-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 38 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 248.0 (M+H)⁺.

Intermediate 39:5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.372mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.101 g, 0.483 mmol) and XPhos-Pd G3 (7.9 mg, 9.3 μmol) were placed ina pressure vial. The reaction mixture was degassed (3× vacuum/Ar), thenTHF (2 mL) and potassium phosphate tribasic (0.5 M aq.) (1.12 mL, 0.557mmol) were added. The reaction mixture was degassed again, and stirredat 100° C. for 1 h. Solvent was removed under reduced pressure. Theobtained residue was dissolved in MeOH (1.0 mL)/THF (1.0 mL), and LiOH(1 M aq.) (1.12 mL, 1.12 mmol) was added. The reaction mixture wasstirred under microwave irradiation at 120° C. for 15 min. The mixturewas acidified with TFA, the solvent was removed under reduced pressure,the residue was purified by preparative HPLC to afford Intermediate 39(0.055 g, 61% yield) as an off-white solid. MS(ESI) m/z; 243.0 (M+H)+,¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.81 (dd, J=7.2, 0.8 Hz, 1H), 8.43 (s,1H), 8.33 (s, 1H), 8.10 (dd, J=1.9, 0.8 Hz, 1H), 8.05 (s, 1H), 7.36 (dd,J=7.3, 2.1 Hz, 1H), 3.90 (s, 3H).

Intermediate 40:6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 40 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 261.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.81 (br s, 1H), 8.41(d, J=1.4 Hz, 1H), 8.28 (s, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.59 (dd,J=9.8, 2.1 Hz, 1H), 3.84 (br d, J=12.9 Hz, 2H), 3.54 (br d, J=11.8 Hz,2H), 3.21 (br d. J=9.4 Hz, 2H), 3.03 (br t, J=12.2 Hz, 2H), 2.87 (s,3H).

Intermediate 41: 6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 41 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 232.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.15 (br s, 1H),8.17 (s, 1H), 7.92 (d J=1.9 Hz, 1H), 7.90 (d, J=9.4 Hz, 1H), 7.29 (dd,J=9.6, 2.2 Hz, 1H), 3.30-3.25 (m, 4H), 1.98 (dt, J=6.6, 3.3 Hz, 4H).

Intermediate 42:(R)-6-(3-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 42 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 250.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.18 (br s, 1H),8.19 (s, 1H), 8.02 (d, J=1.7 Hz, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.32 (dd,J=9.5, 2.1 Hz, 1H), 5.57-5.40 (m, 1H), 3.64-3.51 (m, 2H), 3.46-3.37 (m,2H), 2.33-2.17 (m, 2H); ¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −172.81 (s,1F).

Intermediate 43:(S)-6-(3-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 43 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 250.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19 (s, 1H), 8.02(d, J=1.9 Hz, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.32 (dd, J=9.5, 2.1 Hz, 1H),5.57-5.39 (m, 1H), 3.65-3.50 (m, 2H), 3.46-3.38 (m, 2H), 2.33-2.14 (m,2H). ¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −173.02 (s, 1F).

Intermediate 44:6-(3,3-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 44 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 268.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.24 (br s, 1H),8.22 (s, 1H), 8.10 (d, J=1.7 Hz, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.34 (dd,J=9.5, 2.1 Hz, 1H), 3.75 (t, J=13.3 Hz, 2H), 3.53 (t, J=7.2 Hz, 2H),2.63-2.51 (m, 2H); ¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −96.75 (s, 2F).

Intermediate 45:6-(3-fluoroazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 45 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 235.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.25 (br s, 1H),8.22 (s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.96-7.90 (m, 1H), 7.10 (dd,J=9.4, 2.2 Hz, 1H), 5.60-5.40 (m, 1H), 4.21 (dddd, 1=20.5, 9.4, 5.6, 1.1Hz, 21-), 3.95 (dddd, J=24.0, 9.3, 3.3, 1.1 Hz, 2H); ¹⁹F-NMR: (471 MHz,DMSO-d₆) δ ppm −179.34 (s, 1F).

Intermediate 46:6-(3,3-difluoroazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 46 was prepared by following a similar procedure to thatdescribed for Intermediate 32 employing the appropriate amine. MS(ESI)m/z: 253.9 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.30 (s, 1H), 8.25(s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.16 (dd,J=9.5, 2.1 Hz, 1H), 4.35 (t, J=12.2 Hz, 4H); ¹⁹F-NMR; (471 MHz, DMSO-d₆)δ ppm −98.56 (s, 2F).

Intermediate 47: methyl6-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate

TFA (30 mL) was placed in the round-bottom flask equipped with amagnetic stirred, and the reaction mixture was cooled to 0° C. under Ar.Then, tert-butyl (mesitylsulfonyl)oxycarbamate (6.34 g, 20.00 mmol) wasadded portionwise over 5 min, and the reaction mixture was stirred at 0°C. for 1 h under Ar. Afterwards, the reaction mixture was quenched withice water (100 mL), producing white solid. The reaction mixture wasdiluted with cold water (150 mL), the solid was filtered off, and waswashed with cold water until pH˜7.0. The obtained solid was dissolved inDCM (75.0 mL), and was stirred with Na₂SO₄ at 0° C. for 15 min to removewater. Afterwards, Na₂SO₄ was removed by filtration, and the DCMsolution was added to a cooled (ice bath) solution of3-(benzyloxy)-2-bromopyridine (4.41 g, 16.1 mmol) in DCM (25 mL). Thereaction mixture was stirred at 0° C. for 2 h. Then, ice bath wasremoved, and the reaction mixture was allowed to reach rt and wasstirred at this temperature for 1 h. Solvent was removed under reducedpressure, the residue was dissolved in DMF (100 mL), then methylpropiolate (2.86 mL, 32.1 mmol) and K₂CO₃ (6.66 g, 48.2 mmol) were addedsequentially. The obtained suspension was stirred at rt for 16 h. Thereaction mixture was diluted with EtOAc (500 mL), washed with water(3×250 mL), brine (1×250 mL), dried (Na₂SO₄) and filtered. The residuewas purified by flash chromatography to give Intermediate 47 (0.88 g,15% yield) as an off-white solid. MS(ESI) m/z: 260.8 (M+H)⁺; ¹H NMR (300MHz, CDCl₃) δ ppm 8.45 (s, 1H), 8.15 (d, J=9.6 Hz, 1H), 7.48-7.16 (m,6H), 5.24 (s, 2H), 3.91 (s, 3H).

Intermediate 48:7-cyclopropyl-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 48A: methyl6-(benzyloxy)-7-cyclopropylpyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 47 (350 mg, 0.969 mmol), cyclopropylboronic acid (333 mg,3.88 mmol), palladium(II) acetate (10.98 mg, 0.048 mmol),tricyclohexylphosphonium tetrafluoroborate (35.7 mg, 0.097 mmol) andphosphoric acid, potassium salt (617 mg, 2.91 mmol) were placed in apressure vial, and the mixture was degassed (3× Ar/vacuum). Then, PhMe(10.0 mL) and water (0.2 mL) were added, and the reaction mixture wasdegassed again. Afterwards, the vial was capped, the reaction mixturewas heated to 100° C. for 16 h. Solvent was removed under reducedpressure, and the residue was purified by flash chromatography to giveIntermediate 48A (279 mg, 89% yield) as a white solid. MS(ESI) m/z:323.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.38 (s, 1H), 7.98 (d,J=9.4 Hz, 1H), 7.46-7.38 (m, 4H), 7.37-7.33 (m, 1H), 7.30 (d, J=9.6 Hz,1H), 5.11 (s, 2H), 3.89 (s, 3H), 2.49 (tt, J=8.7, 5.6 Hz, 1H), 1.46-1.41(m, 2H), 1.17-1.11 (m, 2H).

Intermediate 48B: methyl7-cyclopropyl-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 48A (150 mg, 0.465 mmol) was dissolved in THF (4 mL) andMeOH (4 mL), and TEA (0.324 mL, 2.33 mmol) was added. The reactionmixture was degassed (3× vacuum/Ar), then palladium on carbon (10 wt %)(49.5 mg, 0.047 mmol) was added. The reaction mixture was degassedagain, and it was stirred under dihydrogen atmosphere (1 atm; balloon)for 1 h. Pd—C was filtered off using membrane filter, and the filtratewas concentrated to afford Intermediate 48B (103 mg, 95% yield) as awhite solid. MS(ESI) m/z: 233.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.74 (br s, 1H), 8.32 (s, 1H), 7.81 (d, J=9.4 Hz, 1H), 7.30 (d, J=9.4Hz, 1H), 3.79 (s, 3H), 2.48-2.44 (m, 1H), 1.44-1.37 (m, 2H), 1.06-0.98(m, 2H).

Intermediate 48

Intermediate 48B (0.050 g, 0.215 mmol) was suspended in MeCN (2.0 mL),then 2,2-dimethyloxirane (0.288 mL, 3.23 mmol), K₂CO₃ (0.119 g, 0.861mmol) and water (0.133 mL) were added. The reaction mixture was stirredunder microwave irradiation at 120° C. for 30 min. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inMeOH (1 mL)/THF (1 mL), and LiOH (1 M aq.) (0.646 mL, 0.646 mmol) wasadded. The reaction mixture was stirred under microwave irradiation at120° C. for 15 min. Solvent was removed under reduced pressure, theresidue was purified by preparative HPLC to afford Intermediate 48(0.037 g, 59% yield) as a white solid. MS(ESI) m/z: 291.0 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.34 (s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.57 (d,J=9.6 Hz, 1H), 3.81 (s, 2H), 2.63 (tt, J=8.8, 5.6 Hz, 1H), 1.55-1.49 (m,2H), 1.25 (s, 6H), 1.11-1.02 (m, 2H).

Intermediate 49:6-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 49 was prepared by following a similar procedure to thatdescribed for Intermediate 29 employing the appropriate oxirane. MS(ESI)m/z: 359.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.43 (br s, 1H),8.81 (d, J=1.7 Hz, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 8.00 (d, J=9.6 Hz,1H), 7.38 (dd, J=9.6, 2.2 Hz, 1H), 4.54 (s, 2H); ¹⁹F-NMR; (471 MHz,DMSO-d₆) δ ppm −74.51 (s, 3F).

Intermediate 50: 6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 50 was prepared by following a similar procedure to thatdescribed for Intermediate 35 employing the appropriate alkyl/benzylhalide/triflate/methanesulfonate. MS(ESI) m/z: 269.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.38 (s, 1H), 8.66 (d J=1.7 Hz, 1H), 8.30 (s, 1H),7.98 (d, J=9.6 Hz, 1H), 7.50 (d, J=7.2 Hz, 2H), 7.45-7.39 (m, 3H),7.39-7.32 (m, 1H), 5.20 (s, 2H).

Intermediate 51:6-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 51 was prepared by following a similar procedure to thatdescribed for Intermediate 35 employing the appropriate alkyl/benzylhalide/triflate/methanesulfonate. MS(ESI) m/z: 249.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.36 (br s, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.30 (s,1H), 7.96 (d, J=9.6 Hz, 1H), 7.34 (dd, J=9.6, 2.2 Hz, 1H), 5.12 (ddt,J=6.1, 4.0, 1.7 Hz, 1H), 3.93-3.83 (m, 3H), 3.77 (td, J=8.4, 4.4 Hz,1H), 2.32-2.20 (m, 1H), 2.09-1.98 (m, 1H).

Intermediate 52:6-(3,3,3-trifluoro-2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 52 was prepared by following a similar procedure to thatdescribed for Intermediate 35 employing the appropriate alkyl/benzylhalide/triflate/methanesulfonate. MS(ESI) m/z: 291.0 (M+H)⁺; ¹H NMR (500MHz. DMSO-d₆) δ ppm 12.39 (br s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.31 (s,1H), 7.98 (d, J=9.4 Hz, 1H), 7.38 (dd, J=9.6, 2.2 Hz, 1H), 6.72 (br d,J=6.1 Hz, 1H), 4.45 (br s, 1H), 4.30 (dd, J=10.7, 3.9 Hz, 1H), 4.18 (dd,J=10.6, 6.5 Hz, 1H), ¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −75.93 (s, 3F).

Intermediate 53:7-carbamoyl-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

-   -   Intermediate 54:        7-cyano-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylic acid

-   -   Intermediate 54A: methyl        6-(benzyloxy)-7-cyanopyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 47 (350 mg, 0.969 mmol), potassium ferrocyanide, 3H₂O (205mg, 0.485 mmol), XPhos (11.6 mg, 0.024 mmol), Pd-XPhos G3 (20.5 mg,0.024 mmol) were placed in a pressure vial. Then dioxane (10.0 mL) andPotassium acetate (0.1 M aq) (1.21 mL, 0.121 mmol) were added, and thereaction mixture was degassed (3×, vacuum/Ar). The pressure vial wascapped, and the reaction mixture was stirred at 100° C. for 16 h.Additional amounts of XPhos (11.6 mg, 0.024 mmol) and Pd-XPhos G3 (20.5mg, 0.024 mmol) were added, the reaction mixture was degassed, and wasstirred at 125° C. for 18 h. The reaction mixture was diluted withEtOAc, and CELITE® was added. Solvent was removed under reducedpressure, and the residue was purified by flash chromatography (solidloading on CELITE®) to give Intermediate 54A (163 mg, 55% yield) as anoff-white solid. MS(ESI) m/z: 308.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 8.54 (s, 1H), 8.34 (d, J=9.9 Hz, 1H), 7.93 (d, J=9.9 Hz, 1H),7.54-7.49 (m, 2H), 7.48-7.42 (m, 2H), 7.40-7.33 (m, 1H), 5.50 (s, 2H),3.85 (s, 3H).

Intermediate 54B: methyl7-cyano-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 54A (150 mg, 0.488 mmol) was dissolved in THF (4 mL) andMeOH (4 mL), and TEA (0.34 mL, 2.44 mmol) was added. The reactionmixture was degassed (3× vacuum/Ar), then palladium on carbon (10 wt %)(51.9 mg, 0.049 mmol) was added. The reaction mixture was degassedagain, and it was stirred under dihydrogen atmosphere (1 atm; balloon)for 1 h. Pd—C was filtered off using membrane filter, and the filtratewas concentrated to afford crude material, which was further purified byflash chromatography to give Intermediate 54B (50 mg, 47% yield) as ayellow solid. MS(ESI) m/z: 218.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.43 (s, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.43 (d, J=9.6 Hz, 1H), 3.83 (s,3H).

Intermediate 53:7-carbamoyl-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid Intermediate 54:7-cyano-6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 54B (0.050 g, 0.230 mmol) was suspended in MeCN (2.0 mL),then 2,2-dimethyloxirane (0.308 mL, 3.45 mmol), K₂CO₃ (0.127 g, 0.921mmol) and water (0.133 mL) were added. The reaction mixture was stirredunder microwave irradiation at 120° C. for 30 min. Additional amount of2,2-dimethyloxirane (0.308 mL, 3.45 mmol) was added along with THF (1mL), and the reaction mixture was stirred under microwave irradiation at140° C. for 60 min. The reaction mixture was concentrated under reducedpressure, the residue was dissolved in MeOH (1 mL)/THF (1 mL), and LiOH(1 M aq.) (0.276 mL, 0.276 mmol) was added. The reaction mixture wasstirred under microwave irradiation at 120° C. for 15 min. Solvent wasremoved under reduced pressure, the residue was purified by preparativeHPLC to afford Intermediate 53 and Intermediate 54.

Intermediate 53 (5 mg, 7% yield) as an off-white solid. MS(ESI) m/z:294.0 (M+H)⁺; ¹H NMR (500 MHz, THF-d₈) δ ppm 8.27 (s, 1H), 8.17 (d J=9.6Hz, 1H), 7.51 (d, J=9.6 Hz, 1H), 3.96 (s, 2H), 1.23 (s, 6H).

Intermediate 54 (5 mg, 11% yield) as an off-white solid. MS(ESI) m/z:204.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.66 (br s, 1H), 12.22(br s, 1H), 8.36 (s, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.40 (d, J=9.6 Hz,1H).

Intermediate 55:6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 55A: methyl6-(benzyloxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 47 (350 mg, 0.969 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.203 mL, 1.45 mmol) andPd-XPhos G3 (20.5 mg, 0.024 mmol) were placed in a pressure vial. ThenTHF (10 mL) and phosphoric acid, potassium salt (0.5 M aq.) (3.88 mL,1.94 mmol) were added, and the reaction mixture was degassed (3×,vacuum/Ar). The pressure vial was capped, and the reaction mixture wasstirred at 100° C. for 16 h. Additional amounts of Pd-XPhos G3 (20.5 mg,0.024 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.203 mL,1.45 mmol) were added, the reaction mixture was degassed, and wasstirred at 125° C. for 4 h. The reaction mixture was diluted with EtOAc,and CELITE® was added. Solvent was removed under reduced pressure, andthe residue was purified by flash chromatography (solid loading onCELITE®) to give Intermediate 55A (166 mg, 58% yield) as a white solid.MS(ESI) m/z: 297.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.39 (s, 1H),8.01 (d, J=9.6 Hz, 1H), 7.44-7.36 (m, 5H), 7.26 (s, 1H), 5.13 (s, 2H),3.90 (s, 3H), 2.72 (s, 3H).

Intermediate 55B: methyl6-hydroxy-7-methylpyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 55A (150 mg, 0.506 mmol) was dissolved in THF (4 mL) andMeOH (4 mL), and TEA (0.353 mL, 2.53 mmol) was added. The reactionmixture was degassed (3× vacuum/Ar), then palladium on carbon (10 wt %)(53.9 mg, 0.051 mmol) was added. The reaction mixture was degassedagain, and it was stirred under dihydrogen atmosphere (1 atm; balloon)for 1 h. Pd—C was filtered off using membrane filter, and the filtratewas concentrated to afford Intermediate 55B (90 mg, 86% yield) as awhite solid. MS(ESI) m/z: 207.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm9.88 (br s, 1H), 8.34 (s, 1H), 7.85 (d J=8.8 Hz, 1i), 7.37 (d, J=9.4 Hz,1H), 3.80 (s, 3H), 2.60 (s, 3H).

Intermediate 55:6-(2-hydroxy-2-methylpropoxy)-7-methylpyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 55 was prepared from Intermediate 55B by following asimilar procedure to that described for Intermediate 29 employing theappropriate oxirane. MS(ESI) m/z: 265.0 (M+H)+, ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.36 (s, 1H), 7.94 (d, J=9.5 Hz, 1H), 7.61 (d, J=9.7 Hz,1H), 3.82 (s, 2H), 2.67 (s, 3H), 1.24 (s, 6H).

Intermediate 56:6-(2-hydroxy-2-methylpropoxy)-7-(methoxymnethyl)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 56A: methyl6-(benzyloxy)-7-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate

A pressure vial was charged with Intermediate 47 (350 mg, 0.969 mmol),potassium (methoxymethyl)trifluoroborate (295 mg, 1.94 mmol), RuPhos-PdG2 (37.6 mg, 0.048 mmol) and cesium carbonate (947 mg, 2.91 mmol). Themixture was degassed (3×, vacuum/Ar). Then dioxane (10 mL) and water(1,000 mL) were added, and the reaction mixture was degassed again. Thepressure vial was capped, and the reaction mixture was stirred at 100°C. for 18 h. Additional amounts of potassium(methoxymethyl)trifluoroborate (295 mg, 1.938 mmol), SPhos-Pd G2 (34.7mg, 0.048 mmol), and cesium carbonate (947 mg, 2.91 mmol) were added.The reaction mixture was degassed (3× vacuum/Ar), the pressure vial wascapped, and the reaction mixture was stirred at 100° C. for 18 h.Additional amount of SPhos-Pd G2 (34.7 mg, 0.048 mmol) was added, thereaction mixture was degassed, and was stirred at 125° C. for 18 h. Thereaction mixture was diluted with EtOAc, and CELITE®, was added. Solventwas removed under reduced pressure, and the residue was purified byflash chromatography (solid loading on CELITE®) to give Intermediate 56A(61 mg, 19% yield) as an off-white solid. MS(ESI) m/z: 327.0 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.81(d, J=9.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.44-7.38 (m, 2H), 7.37-7.31 (m,1H), 5.28 (s, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.32 (s, 3H).

Intermediate 56B: methyl6-hydroxy-7-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 56A (50 mg, 0.153 mmol) was dissolved in THF (4 mL) andMeOH (4 mL), and TEA (0.107 mL, 0.766 mmol) was added. The reactionmixture was degassed (3× vacuum/Ar), then palladium on carbon (10 wt %)(16.3 mg, 0.015 mmol) was added. The reaction mixture was degassedagain, and it was stirred under dihydrogen atmosphere (1 atm; balloon)for 1 h. Pd—C was filtered off using membrane filter, and the filtratewas concentrated to afford Intermediate 56B (36 mg, 99% yield) as acolorless film. MS(ESI) m/z: 237.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 8.33 (s, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.39 (d, J=9.4 Hz, 1H), 4.90(s, 2H), 3.81 (s, 3H), 3.32 (s, 3H).

Intermediate 56:6-(2-hydroxy-2-methylpropoxy)-7-(methoxyethyl)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 56 was prepared from Intermediate 56B by following asimilar procedure to that described for Intermediate 29 employing theappropriate oxirane. MS(ESI) m/z: 295.0 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.25 (s, 1H), 8.12 (d, J=9.7 Hz, 1H), 7.50 (d, J=9.5 Hz,1H), 5.09 (s, 2H), 3.90 (s, 2H), 3.39 (s, 3H), 1.30 (s, 6H).

Intermediate 57: methyl6-(benzyloxy)-7-((dimethylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

A pressure vial was charged with Intermediate 47 (350 mg, 0.969 mmol),potassium ((dimethylamino)methyl)trifluoroborate (320 mg, 1.938 mmol),RuPhos-Pd G2 (37.6 mg, 0.048 mmol) and cesium carbonate (947 mg, 2.91mmol). The mixture was degassed (3×, vacuum/Ar). Then dioxane (10 mL)and water (1,000 mL) were added, and the reaction mixture was degassedagain. The pressure vial was capped, and the reaction mixture wasstirred at 125° C. for 18 h. Additional amount of RuPhos-Pd G2 (37.6 mg,0.048 mmol) was added, the reaction mixture was degassed (3× Ar/vacuum),and was stirred at 125° C. for 18 h. The reaction mixture was dilutedwith EtOAc, and CELITE® was added. Solvent was removed under reducedpressure, and the residue was purified by flash chromatography (solidloading on CELITE®) to give Intermediate 57 (60 mg, 18% yield) as anoff-white solid. MS(ESI) m/z: 340.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 8.43 (s, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.50(d, J=7.2 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.38-7.31 (m, 1H), 5.25 (s,2H), 4.00 (s, 2H), 3.83 (s, 3H), 2.22 (s, 6H).

Intermediate 58: methyl6-((1,3-difluoropropan-2-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Methyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.520mmol), 1,3-difluoropropan-2-ol (0.090 mL, 1.04 mmol), and1,1′-(azodicarbonyl)dipiperidine (0.394 g, 1.56 mmol) were placed in apressure vial. Then, anhydrous PhMe (5 mL) and tri-N-butylphosphine(0.390 mL, 1.56 mmol) were added, and the reaction mixture was stirredat 140° C. under microwave irradiation for 15 min. The reaction mixturewas quenched with MeOH (1 mL), diluted with EtOAc (50 mL), CELITE® wasadded, and solvent was removed under reduced pressure. The residue waspurified by flash chromatography (solid loading on CELITE®) to giveIntermediate 58 (0.124 g, 88% yield) as a white solid. MS(ESI) m/z:271.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.83 (d, J=1.7 Hz, 1H),8.39 (s, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.49 (dd, J=9.5, 2.3 Hz, 1H),5.11-4.96 (m, 1H), 4.90-4.84 (m, 1H), 4.80-4.72 (m, 2H), 4.67 (dd,J=10.6, 5.1 Hz, 1H), 3.82 (s, 3H); ¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm−231.76 (s, 2F).

Intermediate 59: methyl6-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 59 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 325.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.84 (d, J=2.2 Hz,1H), 8.39 (s, 1H), 8.00 (d, J=9.4 Hz, 1H), 7.53 (dd, J-=9.6, 1.9 Hz,1H), 4.78 (quin, J=4.6 Hz, 1H), 3.82 (s, 3H), 3.30-3.23 (m, 2H),3.19-3.12 (m, 2H), 2.26 (q, J=5.4 Hz, 4H).

Intermediate 60: methyl6-(3,3,3-trifluoropropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 60 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 289.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.70 (d, J=1.9 Hz,1H), 8.38 (s, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.40 (dd, J=9.6, 2.2 Hz, 1H),4.33 (t, J=5.9 Hz, 2H), 3.82 (s, 3H), 2.85 (qt, J=11.3, 5.8 Hz, 2H);¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −63.03 (s, 3F).

Intermediate 61: methyl6-((4,4-difluorocyclohexyl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 61 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 311.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.78 (d, J=1.7 Hz,1H), 8.38 (s, 1H), 8.03-7.96 (m, 1H), 7.47 (dd, J=9.6, 2.2 Hz, 1H), 4.69(br dd, J=6.3, 3.3 Hz, 1H), 3.82 (s, 3H), 2.17-2.04 (m, 2H), 2.04-1.92(m, 4H), 1.91-1.80 (m, 2H).

Intermediate 62: methyl6-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 62 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 277.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-δ₆) δ ppm 8.75 (s, 1H), 8.37(s, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.44 (dd, J=9.6, 2.2 Hz, 1H), 4.67 (tt,J=8.7, 4.1 Hz, 1H), 3.87 (dt, J=11.7, 4.3 Hz, 2H), 3.82 (s, 3H), 3.49(ddd, J=11.8, 9.4, 2.8 Hz, 2H), 2.07-1.99 (m, 2H), 1.68-1.56 (m, 2H).

Intermediate 63: methyl6-((1-(methoxycarbonyl)azetidin-3-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 63 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 306.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.47 (d, J=1.7 Hz,1H), 8.38 (s, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.42 (dd, J=9.6, 2.2 Hz, 1H),5.15-5.09 (m, 1H), 4.46-4.39 (m, 2H), 3.97-3.89 (m, 2H), 3.82 (s, 3H),3.58 (s, 3H).

Intermediate 64: methyl6-(3,3-difluorocyclobutoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 64 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 283.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.56 (d, J=1.7 Hz,1H), 8.38 (s, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.41 (dd, J=9.6, 2.2 Hz, 1H),4.92-4.84 (m, 1H), 3.82 (s, 3H), 3.29-3.24 (m, 2H), 2.83-2.71 (m, 2H);¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −83.24 (s, 1F), −92.94 (s, 1F).

Intermediate 65: methyl6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 65 was prepared by following a similar procedure to thatdescribed for Intermediate 58 employing the appropriate alcohol. MS(ESI)m/z: 319.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.63 (d, J=1.7 Hz,1H), 8.36 (s, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.43 (dd, J=9.5, 2.3 Hz, 1H),4.28-4.23 (m, 2H), 4.17 (q, J=9.4 Hz, 2H), 4.00-3.93 (m, 2H), 3.82 (s,3H); ¹⁹F-NMR (471 MHz, DMSO-d₆) δ ppm −72.89 (s, 3F).

Intermediate 66: methyl6-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

Methyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.100 g, 0.520mmol),

-   2-(chloromethyl)-5-cyclopropyl-1,3,4-thiadiazole (0.136 g, 0.781    mmol), and K₂C₀₃ (0.144 g, 1.04 mmol) were placed in a pressure    vial. Then, anhydrous MeCN (5 mL) was added, and the reaction    mixture was stirred at 120° C. under microwave irradiation for 15    min. The reaction mixture was diluted with EtOAc (25 mL), filtered,    and the solvent was removed under reduced pressure. The residue was    purified by flash chromatography to give Intermediate 66 (40 mg, 23%    yield) as a off-white solid. MS(ESI) m/z: 331.0 (M+H)⁺; ¹H NMR (500    MHz, DMSO-d₆) δ ppm 8.82 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 8.01 (d,    J=9.7 Hz, 1H), 7.48 (dd, J=9.5, 2.2 Hz, 1H), 5.63 (s, 2H), 3.82 (s,    3H), 2.59-2.52 (m, 1H), 1.25-1.18 (m, 2H), 1.06-1.01 (m, 2H).

Intermediate 67: methyl6-(benzyloxy)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate

Intermediate 67A: 3-(benzyloxy)-2-(trifluoromethyl)pyridine

2-(trifluoromethyl)pyridin-3-ol (0.500 g, 3.07 mmol) was suspended inMeCN (10 mL), then (bromomethyl)benzene (0.419 mL, 3.53 mmol), K₂CO₃(1.06 g, 7.66 mmol) and water (0.67 mL) were added. The reaction mixturewas stirred under microwave irradiation at 120° C. for 30 min. Thereaction mixture was diluted with EtOAc (50 mL), CELITE® was added, andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography (solid loading on CELITE®) to give Intermediate67A (0.724 g, 93% yield) as a colorless oil. MS(ESI) m/z: 254.0 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.26 (dd, J=4.0, 1.5 Hz, 1H), 7.45-7.37(m, 6H), 7.36-7.31 (m, 1H), 5.22 (s, 2H); ¹⁹F-NMR: (471 MHz, CDCl₃) δppm −66.35 (s, 3F).

Intermediate 67

TFA (3 mL) was placed in the round-bottom flask equipped with a magneticstirred, and the reaction mixture was cooled to 0° C. under Ar. Then,tert-butyl (mesitylsulfonyl)oxycarbamate (0.778 g, 2.47 mmol) was addedportionwise over 5 min, and the reaction mixture was stirred at 0° C.for 1 h under Ar. Afterwards, the reaction mixture was quenched with icewater (10 mL), producing white solid. The reaction mixture was dilutedwith cold water (15 mL), the solid was filtered off, and was washed withcold water until pH-7.0. The obtained solid was dissolved in DCM (7.50mL), and was stirred with MS 4A (beads) at 0° C. for 15 min to removewater. Afterwards, DCM solution cannulated from the beads, to a cooled(ice bath) solution of Intermediate 67A (0.500 g, 1.98 mmol) in DCM (2.5mL). The reaction mixture was stirred at 0° C. for 2 h. Then, ice bathwas removed, and the reaction mixture was allowed to reach it and wasstirred at this temperature for 16 h. Additional batch of MSH wasprepared as described above, and was added to the reaction mixture at 0°C. The reaction mixture was allowed to reach rt and stirred foradditional 16 h. Solvent was removed under reduced pressure, the residuewas dissolved in DMF (10 mL), then methyl propiolate (0.351 mL, 3.95mmol) and K₂CO₃ (0.819 g, 5.92 mmol) were added sequentially. Theobtained suspension was stirred at it for 16 h. The reaction mixture wasfiltered, and the solution was purified by preparative HPLC to affordIntermediate 67 (24 mg, 3% yield) was obtained as an off-white solid.MS(ESI) m/z: 351.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.53 (s, 1H),8.34 (d, J=9.9 Hz, 1H), 7.97 (d, J=9.9 Hz, 1H), 7.50-7.44 (m, 2H),7.44-7.39 (m, 2H), 7.38-7.32 (m, 1H), 5.40 (s, 2H), 3.86 (s, 3H);¹⁹F-NMR: (471 MHz, DMSO-d₆) δ ppm −59.24 (s, 3F).

Intermediate 68:6-bromo-1-(2-hydroxy-2-methylpropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl-1H-indazole-3-carboxamide

Intermediate 68A:6-bromo-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid

Intermediate 68A was prepared by following a similar procedure to thatdescribed for Intermediate 29 employing the appropriate oxirane. MS(ESI)m/z: 312.9 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.06 (dd, J=8.7,0.6 Hz, 1H), 8.03-8.01 (m, 1H), 7.42 (dd J=8.6, 1.5 Hz 1H), 4.43 (s,2H), 1.25 (s, 6H).

Intermediate 68

Intermediate 68A (269 mg, 0.859 mmol) was dissolved in anhydrous DMF (5mL), then DIEA (0.300 mL, 1.72 mmol) and HATU (283 mg, 0.744 mmol) wereadded. After stirring for 30 min at rt, the obtained solution was addedto a solution of Intermediate 2, HCl (167 mg, 0.572 mmol) and DIEA(0.300 mL, 1.717 mmol) in anhydrous DMF (5 mL), and the reaction mixturewas stirred at rt for 1 h. The reaction mixture was quenched with MeOH(0.5 mL), diluted with EtOAc (100 mL), washed with water (2×50 mL),brine (1×50 mL), and dried (Na₂SO₄). EtOAc was removed under reducedpressure and the residue was purified by flash chromatography to giveIntermediate 68 (295 mg, 94% yield) as a colorless glass, whichsolidified upon standing. MS(ESI) m/z: 550.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.46 (s, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.26 (dd, J=8.0,0.8 Hz, 1H), 8.10 (d, J=1.1 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.98-7.85(m, 2H), 7.86-7.80 (m, 1H), 7.36 (dd, J=8.7, 1.5 Hz, 1H), 4.70 (s, 1H),4.37 (s, 2H), 4.03 (q, J=7.2 Hz, 1H), 3.90 (quin, J=8.5 Hz, 1H),2.65-2.54 (m, 2H), 2.45-2.31 (m, 4H), 2.26-2.12 (m, 2H), 1.15 (s, 6H).

Intermediate 69:4-(6-amino-2-fluorospiro[3.3]heptan-2-yl)phthalazin-1(21)-one

Intermediate 69A: tert-butyl(6-hydroxy-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 1A (2.46 g, 7.20 mmol) was placed in a round-bottom flask,then dioxane (36.0 mL) was added, and the mixture was stilled untilcomplete dissolution (˜5 min). Afterwards, hydrazine (2.26 mL, 72.0mmol) was added, and the reaction mixture was stirred under Ar at rt for2 h. The reaction mixture was heated to 65° C., and was stirred at thistemperature for 5 h (at this point the reaction mixture becameheterogeneous). The reaction mixture was cooled to rt, and the solventwas removed under reduced pressure, and the residue was co-evaporatedwith THF (2×50 mL). The residue was dissolved THF/MeOH, CELITE® wasadded, the solvent was removed under reduced pressure, and the residuewas purified by flash chromatography (solid loading on CELITE®) toafford Intermediate 1B (1.43 g, 56% yield) as a white solid (eluted at70% EtOAc) and Intermediate 69A (0.235 g, 9% yield) was obtained as acolorless foam (eluted at ˜85% EtOAc).

Intermediate 69A: MS(ESI) m/z: 372.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 12.47 (s, 1H), 8.26 (dd, J=7.8, 1.0 Hz, 1H), 8.11 (d, J=7.7 Hz, 1H),7.88 (ddd, J=8.3, 7.1, 1.4 Hz, 1H), 7.84-7.78 (m, 1H), 6.99 (br d, J=7.7Hz, 1H), 5.87 (s, 1H), 3.83-3.70 (m, 1H), 2.90 (br dd, J=11.7, 3.2 Hz,1H), 2.76 (br dd, J=11.8, 3.3 Hz, 1H), 2.40 (br d. J=11.3 Hz, 1H), 2.31(br d, J=11.8 Hz, 2H), 2.02-1.95 (m, 1H), 1.74 (t, J=9.8 Hz, 1H), 1.34(s, 9H).

Intermediate 69B: tert-butyl(6-fluoro-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 69A (50 mg, 0.135 mmol) was dissolved in anhydrous DCM (2mL), and the reaction mixture was cooled to 0° C. (ice bath),bis(2-methoxyethyl)aminosulfur trifluoride (0.074 mL, 0.404 mmol) wasadded dropwise, the reaction mixture was stirred at 0° C. for 1 h, andthen was allowed to reach rt in the course of 14 h. Reaction mixture wasquenched with MeOH (1 mL). The solvent was removed under reducedpressure and the residue was purified by flash chromatography toIntermediate 69B (50 mg, 99% yield) as a white solid. MS(ESI) m/z: 374.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.78 (s, 1-), 8.31 (dd, J=8.1,1.2 Hz, 1H), 7.98-7.93 (m, 1H), 7.91-7.85 (m, 2H), 7.06 (br d, J=7.4 Hz,1H), 3.87-3.77 (m, 1H), 3.06-2.97 (m, 1H), 2.89 (td, J=13.7, 4.0 Hz,1H), 2.78-2.71 (m, 1H), 2.71-2.64 (m, 1H), 2.64-2.58 (m, 1H), 2.43-2.34(m, 1H), 2.12-2.04 (m, 1H), 1.87-1.78 (m, 1H), 1.35 (s, 9H).

Intermediate 69:4-(6-amino-2-fluorospiro[3.3]heptan-2-yl)phthalazin-1(2H)-one(2H)-one

Intermediate 69B was dissolved in TFA (3 mL), and the reaction mixturewas stirred at rt for 15 min. Solvent was removed under reducedpressure, and co-evaporated with Et₂₀ (3×3 mL) to give Intermediate 69,TFA (52 mg, 0.134 mmol, 100% yield) as an off-white solid. MS(ESI) m/z:274.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8 ppm 12.80 (s, 1H), 8.54(br s, 1H), 8.36-8.26 (m, 1H), 8.00-7.93 (m, 1H), 7.92-7.87 (m, 4H),3.05 (td, J=13.5, 4.4 Hz, 1H), 2.97 (td, J=13.7, 4.3 Hz, 1H), 2.75 (ddd,J=33.5, 20.8, 12.8 Hz, 2H), 2.47-2.43 (m, 1H), 2.30 (dd, J=12.0, 8.4 Hz,1H), 2.16 (ddd, J=11.8, 7.3, 4.8 Hz, 1H), 2.05 (dd, J=11.8, 8.5 Hz, 1H);¹⁹F-NMR: (471 MHz, DMSO-d₆) 5 ppm −129.78 (s, 1F).

Intermediate 70:6-bromo-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

6-Bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (180 mg, 0.749 mmol)was dissolved in anhydrous DMF (5 mL), then DIEA (0.302 mL, 1.73 mmol)and HATU (252 mg, 0.662 mmol) were added. After stirring for 30 min atrt, the obtained solution was added to a solution of Intermediate 2, HCl(168 mg, 0.576 mmol) and DIEA (0.302 mL, 1.73 mmol) in anhydrous DMF (5mL), and the reaction mixture was stirred at rt for 1 h. The reactionprogress was checked by LC-MS: complete conversion to the targetproduct. The reaction mixture was quenched with MeOH (0.5 mL), dilutedwith EtOAc (100 mL), washed with water (2×50 mL), brine (1×50 mL), anddried (Na₂SO₄). EtOAc was removed under reduced pressure and the residuewas purified by flash chromatography to give Intermediate 70 (274 mg,99% yield) as a colorless glass, which solidified upon standing. MS(ESI)m/z: 478.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.17(dd, J=1.7, 0.8 Hz, 1H), 8.57 (s, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.26 (dd,J=7.7, 0.8 Hz, 1H), 8.14 (d, J=9.4 Hz, 11-), 7.94-7.90 (m, 1H),7.90-7.87 (m, 1H), 7.86-7.81 (m, 1H), 7.58 (dd, J=9.5, 1.8 Hz, 1H), 4.38(sxt, J=8.1 Hz, 1H), 3.91 (quin, J=8.5 Hz, 1H), 2.64 (ddd, J=10.7, 7.3,5.4 Hz, 1H), 2.58 (ddd, J=11.0, 8.1, 3.2 Hz, 1H), 2.45-2.34 (m, 3H),2.29-2.19 (m, 2H), 2.05 (dd, J=11.0, 9.1 Hz, 1H).

Intermediate 71:6-(2-hydroxyethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Intermediate 71A:6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 71A was prepared by following a similar procedure to thatdescribed for Intermediate 29 employing the appropriate oxirane. MS(ESI)m/z: 223.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) ppm 12.21 (br s, 1H), 8.57(d, J=1.7 Hz, 1H), 8.29 (s, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.36 (dd,J=9.5, 2.1 Hz, 1H), 4.94 (br s, 1H), 4.13-4.03 (m, 2H), 3.74 (br s, 2H).

Intermediate 71

Intermediate 2, HCl (382 mg, 1.31 mmol) and Intermediate 71A (320 mg,1.440 mmol) were suspended in anhydrous DMF (12 mL). Then DIEA (0.915mL, 5.24 mmol) and HATU (548 mg, 1.44 mmol) were added and the reactionmixture was stirred at rt for 1 h. The reaction mixture was quenchedwith MeOH (0.75 mL), diluted with EtOAc (450 mL), washed with water(2×100 mL), brine (1×50 mL), and dried (Na₂SO₄). EtOAc was removed underreduced pressure and the residue was purified by flash chromatography togive Intermediate 71 (132 mg, 22% yield) as a colorless glass, whichsolidified upon standing. MS(ESI) m/z: 460.0 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.46 (s, 1H), 8.50-8.41 (m, 2H), 8.29-8.19 (m, 2H), 8.08(d, J=9.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.81 (m,1H), 7.26 (dd, J=9.6, 2.2 Hz, 1H), 4.98-4.89 (m, 1H), 4.42-4.33 (m, 1H),4.06 (br t, J=4.7 Hz, 2H), 3.91 (quin, J=8.5 Hz, 1H), 3.79-3.70 (m, 2H),2.67-2.60 (m, 1H), 2.60-2.54 (m, 1H), 2.43-2.34 (m, 3H), 2.28-2.18 (m,2H), 2.08-2.01 (m, 1H).

Intermediate 72:6-(2-iodoethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

To a solution/suspension of Intermediate 71 (132 mg, 0.287 mmol) in MeCN(6 mL) and THF (9 mL) was sequentially added triphenylphosphine (98 mg,0.373 mmol), iodine (102 mg, 0.402 mmol) and imidazole (29.3 mg, 0.431mmol) at 0° C., and the reaction mixture was stirred at the sametemperature for 30 min. The cooling bath was removed, and the reactionmixture was stirred at it for 1 h. Solvent was removed under reducedpressure, and the residue was redissolved in anhydrous DMF (4 mL). Thesolution was cooled to 0° C., and triphenylphosphine (98 mg, 0.37 mmol),iodine (102 mg, 0.402 mmol) and imidazole (29.3 mg, 0.431 mmol) wereadded sequentially. The reaction mixture was stirred at 0° C. for 30min. The cooling bath was removed, and the reaction mixture was stirredat rt for 1 h. The reaction mixture was quenched with McOH/H₂O/TFA,acidified with TFA and purified by preparative HPLC to affordIntermediate 72 (100 mg, 61% yield) as an off-white solid. MS(ESI) m/z:569.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.50 (d,J=1.7 Hz, 1H), 8.46 (s, 1H), 8.28-8.22 (m, 2H), 8.09 (d, J=9.6 Hz, 1H),7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.28 (dd,J=9.6, 2.2 Hz, 1H), 4.37 (br d, J=7.7 Hz, 1H), 4.34 (t, J=6.1 Hz, 2H),3.91 (quin, J=8.5 Hz, 1H), 3.56 (t J=5.9 Hz, 2H), 2.67-2.61 (m, 1H),2.60-2.54 (m, 1H), 2.45-2.35 (m, 3H), 2.27-2.17 (m, 2H), 2.08-2.01 (m,1H).

Intermediate 73:N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(3-oxopropyl)pyrazolo_([)1,5-a]pyridine-3-carboxamide

A solution of Intermediate 70 (50 mg, 0.105 mmol), prop-2-en-1-ol (8.53μl, 0.125 mmol), dihydrogendi-mu-chlorotetrakis(diphenylphosphinito-kp)dipalladate(2-) (5.7 mg,5.23 μmol) and sodium acetate (11.2 mg, 0.136 mmol) in anhydrous DMF (1mL) was degassed (3× vacuum/Ar) at it, and then was stirred at 90° C.for 6 h under Ar atmosphere. The reaction mixture was diluted with EtOAc(50 mL), washed with water (2×15 mL), brine (1×20 mL), and dried(Na₂SO₄). EtOAc was removed under reduced pressure and the residue waspurified by flash chromatography to give Intermediate 73 (20 mg, 42%yield). MS(ESI) m/z: 456.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 9.74 (t, J=1.0 Hz, 1H), 8.50 (d, J=3.9 Hz, 1H), 8.28-8.25 (m,1H), 8.25-8.22 (m, 1H), 8.12-8.08 (m, 1H), 7.95-7.90 (m, 1H), 7.90-7.86(m, 1H), 7.86-7.82 (m, 1H), 7.37 (ddd, J=14.2, 9.2, 1.4 Hz, 1H),4.46-4.34 (m, 2H), 3.91 (quin, J=8.5 Hz, 1H), 2.94-2.84 (m, 2H),2.71-2.61 (m, 2H), 2.58 (ddd, J=10.8, 8.0, 3.2 Hz, 1H), 2.46-2.33 (m,2H), 2.28-2.18 (m, 2H), 2.05 (dd, J=11.1, 9.2 Hz, 1H), 1.88-1.76 (m,1H).

Intermediate 74:5-bromo-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)isoindoline-2-carboxamide

Intermediate 2, HCl (300 mg, 1.028 mmol) was suspended in THF (15 mL),and DIEA (0.449 mL, 2.57 mmol) was added. The reaction mixture wascooled to 0° C., and 4-nitrophenyl carbonochloridate (249 mg, 1.23 mmol)was added. The reaction mixture was stirred at 0° C. for 30 min, then5-bromoisoindoline (407 mg, 2.06 mmol) and DIEA (0.449 mL, 2.57 mmol)were added. The cooling bath was removed, and the reaction mixture wasstirred at 50° C. for 16 h. The reaction mixture was cooled to it,quenched with MeOH (3 mL) and concentrated. The residue was purified byflash chromatography (30-100% EtOAc/DCM gradient) to afford Intermediate74 (400 mg, 81% yield) as a light yellow solid. MS(ESI) m/z: 481.2(M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.45 (s, 1H), 8.25 (dd, J=7.8,1.0 Hz, 1H), 7.94-7.89 (m, 1H), 7.88-7.85 (m, 1H), 7.85-7.80 (m, 1H),7.54 (s, 1H), 7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.47(d, J=7.7 Hz, 1H), 4.55 (br d. J=20.9 Hz, 4H), 4.15-4.05 (m, 1H), 3.88(quin, J=8.5 Hz, 1H), 2.58-2.53 (m, 2H), 2.40-2.28 (m, 3H), 2.19-2.12(m, 21-), 1.98-1.93 (m, 1H).

Intermediate 75: tert-butyl((aR)-6-(3-(dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 2A (2.00 g, 5.63 mmol) and 1,1′-(azodicarbonyl)dipiperidine(3.55 g, 14.1 mmol) were placed in a pressure vial. Then, PhMe (50 mL),dicyclopropylmethanol (1.33 mL, 11.3 mmol) and tri-N-butylphosphine(3.51 mL, 14.17 mmol) were added, and the reaction mixture was stirredat 50° C. under Ar atmosphere for 2 d. Additional dicyclopropylmethanol(1.32 mL, 11.2 mmol) was added, followed by1,1′-(azodicarbonyl)dipiperidine (3.55 g, 14.1 mmol) andtri-N-butylphosphine (3.51 mL, 14.1 mmol), and the reaction mixture wasstirred at 50° C. for 3 h. The reaction mixture was quenched with MeOH(15 mL), diluted with EtOAc, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (0-20%EtOAc/DCM gradient) to give Intermediate 75 (1.299 g, 2.89 mmol, 51%yield) as a colorless foam. MS(ESI) m/z: 450.4 (M+H)⁺; ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 8.27 (dd, J=8.3, 1.1 Hz, 1H), 7.90 (dd, J=7.3, 1.8 Hz,1H), 7.86-7.80 (m, 2H), 3.91 (quin, J=8.0 Hz, 1H), 3.86-3.77 (m, 1H),3.67 (br t, J=9.2 Hz, 1H), 2.58-2.52 (m, 1H), 2.48-2.42 (m, 1H),2.41-2.32 (m, 3H), 2.16-2.09 (m, 1H), 2.03-1.97 (m, 1H), 1.87 (br t,J=9.9 Hz, 1H), 1.54-1.45 (m, 2H), 1.26-1.19 (m, 2H), 1.18-1.12 (m, 2H),0.69-0.61 (m, 2H), 0.54 (dq, J=9.6, 4.8 Hz, 2H), 0.35-0.27 (m, 2H),0.20-0.11 (m, 2H).

Intermediate 76:4-((aR)-6-aminospiro[3.3]heptan-2-yl)-2-(dicyclopropylmethyl)phthalazin-1(2H)-one(2H)-one

Intermediate 75 (1.30 g, 2.89 mmol) was dissolved in MeOH (5 mL), andwater (15 mL) was added to the reaction mixture. The reaction mixturewas stirred under microwave irradiation at 160° C. for 90 min. Thereaction mixture was diluted with MeCN, and solvent was removed underreduced pressure. The residue was co-evaporated with MeCN (3×), then waspurified by flash chromatography (1-15% MeOH/DCM gradient) to affordIntermediate 76 (0.205 g, 20% yield) as a colorless foam. MS(ESI) m/z:350.3 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.30-8.26 (m, 1H),7.95-7.89 (m, 1H), 7.87-7.81 (m, 2H), 3.93 (quin, J=7.8 Hz, 1H), 3.68(br t, J=9.2 Hz, 1H), 3.54 (quin, J=8.0 Hz, 1H), 3.17 (s, 1H), 2.62-2.55(m, 1H), 2.47-2.37 (m, 3H), 2.26-2.14 (m, 2H), 2.04 (dd, J=11.7, 8.7 Hz,1H), 1.54-1.44 (m, 2H), 0.69-0.61 (m, 2H), 0.56 (dq, J=9.7, 4.8 Hz, 2H),0.36-0.27 (m, 2H), 0.21-0.12 (m, 2H).

Intermediate 77:6-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

To a suspension of ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate(70 mg, 0.34 mmol) in MeCN (2 mL), were added tert-butyl2-bromoisobutyrate (0.076 mL, 0.41 mmol) and cesium carbonate (166 mg,0.509 mmol). The reaction mixture was stirred at rt for 1 h, then at120° C. for 15 min. The mixture was concentrated. The residue wassuspended in THF (3 mL), then was treated with 1M aq. LiOH (0.679 mL,0.679 mmol) and a MeOH (0.5 mL). The mixture was stirred was heated in amicrowave reactor at 120° C. for 15 min. The mixture was partiallyevaporated, then was cooled to 0° C., and treated with TFA (0.13 mL, 1.7mmol). The mixture was purified by preparative HPLC to affordIntermediate 77 (59 mg, 54% yield) as a white solid. MS(ESI) m/z: 321.1(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (br s, 1H), 8.39 (dd, J=2.2,0.7 Hz, 1H), 8.34 (s, 1H), 8.00 (dd, J=9.6, 0.6 Hz, 1H), 7.36 (dd,J=9.6, 2.1 Hz, 1H), 1.53 (s, 6H), 1.42 (s, 9H).

Intermediate 78.2-((3-(ethoxycarbonyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)acetic acid

To a suspension of ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate(50 mg, 0.24 mmol) in MeCN (2 mL), were added tert-butyl 2-bromoacetate(0.043 mL, 0.29 mmol) and cesium carbonate (87 mg, 0.27 mmol). Thereaction mixture was stirred at rt for 2 h. The mixture wasconcentrated. The residue was suspended in THF (2 mL), then was treatedwith IM aq. LiOH (0.485 mL, 0.485 mmol) and MeOH (0.5 mL). The mixturewas stirred at rt for 2 h. The mixture was acidified with 1N HCl (˜0.5mL) and the volatiles were evaporated. The precipitate was collected byfiltration and was dried overnight in a vacuum oven at 50° C., to affordIntermediate 78 (53.7 mg, 84% yield) as a white solid. MS(ESI) m z:265.0 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.60 (d, J=2.0Hz, 1H), 8.36 (s, 1H), 7.98 (d, J=9.5 Hz, 1H), 7.45 (dd, J=9.7, 2.2 Hz,1H), 4.80 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).

Intermediate 79. ethyl6-((3,5-dimethylphenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate

A solution of ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (500mg, 2.22 mmol) in DMA (15 mL) was purged with N₂ for 15 min. To thismixture were added 3,5-dimethylaniline (537 mg, 4.43 mmol), Pd₂(dba)₃(406 mg, 0.443 mmol), XANTPHOS (513 mg, 0.886 mmol) and cesium carbonate(2.89 g, 8.86 mmol). The reaction vessel was sealed and heated at 125°C. for 1.5 h. The reaction was cooled to r.t. and filtered throughCELITE®. EtOAc (100 mL) was added to dilute the filtrate. The solutionwas washed with water (3×). The organic layer was dried (Na₂SO₄),filtered and concentrated to provide a crude product. The product waspurified using silica gel chromatography (0 to 100% EtOAc/hexanesgradient) to afford Intermediate 79 (340 mg, 49%) as a brown solid.MS(ESI) m z: 311.3 (M+H)⁺.

Intermediate 80.6-((3,5-dimethylphenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid

To a solution of Intermediate 79 (340 mg, 1.10 mmol) in THF (22 mL) andMeOH (11 mL) at 0° C., was carefully add 3M aq. LiOH (11.5 mL, 34.5mmol). The mixture was warmed to room temperature and stirred for 2hours. The mixture was poured into 100 mL 0.01 M NaOH (aq). The aqueouswas washed with hexanes and 1:1 hexanes:EtOAc. The aqueous phase wasacidified and extracted with EtOAc (4×). The organic phase wasconcentrated to provide Intermediate 80 (250 mg, 81%), which was usedwithout further purification. MS(ESI) m/z: 283.1 (M+H)⁺.

Intermediate 81, methyl 6-aminobenzo[d]isoxazole-3-carboxylate

To a solution of methyl 6-nitro-1,2-benzisoxazole-3-carboxylate (98 mg,0.44 mmol) in Methanol (5 mL) and water (2.5 mL), was added ammoniumchloride (118 mg, 2.21 mmol) and zinc (144 mg, 2.21 mmol). The resultingsuspension was heated at 70° with vigorous stirring for 2 h. Thereaction mixture was filtered through CELITE®, diluted with brine (200mL), and the resulting solution was extracted with ethyl acetate (200mL). The organic layer was washed with of brine (3×), dried (MgSO₄) andconcentrated. The residue was purified by flash chromatography (0-10%MeOH/CH₂Cl gradient) to afford Intermediate 81 (8 mg, 9% yield). MS(ESI)m/z: 193.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.83 (dd, J=8.5, 0.6Hz, 1H), 6.80-6.77 (m, 1H), 6.75 (dd, J=8.6, 2.0 Hz, 1H), 4.27-4.09 (m,2H), 4.05 (s, 3H).

Intermediate 82, methyl 6-acetamidobenzo[d]isoxazole-3-carboxylate

To a mixture of Intermediate 81 (8 mg, 0.042 mmol) and DIEA (10 μl,0.057 mmol) in DCM (1 mL) at 0° C., was added acetyl chloride (4 μL,0.06 mmol). The mixture was stirred at rt for 30 min, then was quenchedwith water and extracted with EtOAc. The organic layer was concentratedand the product was purified by flash chromatography (0-100%EtOAc/hexanes gradient) to afford Intermediate 82 (7 mg, 72% yield) as awhite solid. MS(ESI) m/z: 235.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ8.31 (d, J=1.1 Hz, 1H), 7.98 (dd, J=8.6, 0.7 Hz, 1H), 7.42 (dd, J=8.7,1.7 Hz, 1H), 4.05 (s, 3H), 2.18 (s, 3H).

Intermediate 83. 6-bromobenzo[c]isoxazole-3-carboxylic acid

Methyl 2-(4-bromo-2-nitrophenyl)acetate (1.64 g, 5.98 mmol) in H₂SO₄ (10mL, 188 mmol) was heated at 110° C. for 2 h. The dark brown solution waspoured onto ice, then was extracted with EtOAc (2×). The combine organiclayer was concentrated and the residue was purified by flashchromatography (0-100% EtOAc/hexanes gradient) to afford Intermediate 83(468 mg, 32% yield) as an orange solid. MS(ESI) m/z: 243.9 (M+H)⁺; ¹HNMR (400 MHz, methanol-d₄) δ 8.01 (t, J=1.2 Hz, 1H), 7.89 (dd, J=9.2,0.9 Hz, 1H), 7.37 (dd, J=9.1, 1.4 Hz, 1H).

Intermediate 84, methyl 6-bromobenzo[c]isoxazole-3-carboxylate

To a solution of Intermediate 83 (200 mg, 0.826 mmol) in CH₂C₂ (10 mL)and MeOH (1 mL) at 0° C., was added 2M TMS-diazomethane (0.537 mL, 1.074mmol), dropwise. The mixture was allowed to slowly warm to rt and wasstirred for 1 h. The mixture was concentrated and the residue waspurified by flash chromatography (0-100% EtOAc/hexanes gradient) toafford Intermediate 84 (185 mg, 0.723 mmol, 87% yield) as pale yellowsolid. MS(ESI) m/z: 255.9 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.95(t, J=1.2 Hz, 1H), 7.83 (dd, J=9.2, 0.9 Hz, 1H), 7.30 (dd, J=9.1, 1.4Hz, 1H), 4.09 (s, 3H)

Intermediate 85, methyl6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[c]isoxazole-3-carboxylate

To a sealable vial containing a suspension of potassium acetate (138 mg,1.406 mmol), Intermediate 84 (120 mg, 0.469 mmol), and5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (138 mg, 0.609 mmol)in DMSO (1 mL), purged with Ar for 10 min, was added1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)dichloromethane complex (34.3 mg, 0.047 mmol). The vial was capped andthe reaction was heated and stirred at 80° C. for 1 h. The mixture wasdiluted with water and extracted with EtOAc (2×). The organic phase wasconcentrated and the residue was purified by flash chromatography(0-100% EtOAc/hexanes gradient) to afford Intermediate 85 (65 mg, 48%yield) as a white solid. MS(ESI) m/z: 222.0 (M(boronic acid)+H)⁺; ¹H NMR(400 MHz, THF) δ 10.81 (s, 1H), 8.15 (s, 1H), 7.84 (dd, J=8.8, 1.1 Hz,1H), 7.57 (dd, J=8.8, 0.4 Hz, 1H), 4.02 (s, 3H), 3.82 (s, 4H), 1.03 (s,6H).

Intermediate 86, methyl 6-hydroxybenzo[c]isoxazole-3-carboxylate

A homogeneous mixture of Intermediate 85 (65 mg, 0.225 mmol) in THF (2mL) at rt was treated with a mixture of sodium perborate tetrahydrate(41.5 mg, 0.270 mmol) in water (2 mL) for 2.5 h. The reaction wasquenched with satd, aq, NH₄Cl, then was extracted with EtOAc (2×). Thecombined organic phase was dried (MgSO₄) and concentrated. The residuewas purified by flash chromatography (0-100% EtOAc/hexanes gradient) toafford Intermediate 86 (40 mg, 92% yield) as a yellow solid. MS(ESI)m/z; 194.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.79 (dd, J=9.4, 0.8Hz, 1H), 6.94 (dd, J=9.4, 1.9 Hz, 1H), 6.77 (dd, J=1.9, 0.8 Hz, 1H),4.06 (s, 3H).

Intermediate 87.6-(2-hydroxy-2-methylpropoxy)benzo[c]isoxazole-3-carboxylic acid

To a solution of Intermediate 86 (40 mg, 0.207 mmol) in acetonitrile (2mL) and water (0.13 mL), were added K₂CO₃ (114 mg, 0.828 mmol) and2,2-dimethyloxirane (0.280 mL, 3.11 mmol) at rt. The reaction was heatedwith microwave at 120° C. for 30 min. The reaction mixture was dilutedwith EtOAc, acidified with 1.0 N HCl, washed with H₂O and brine. Theorganic phase was dried (MgSO₄) and concentrated. The product waspurified by preparative HPLC to afford Intermediate 87 (13 mg, 25%yield) as a yellow foam. MS(ESI) m/z: 252.1 (M+H)⁺; ¹H NMR (400 MHz,THF) δ 7.80 (dd, J=9.4, 0.8 Hz, 1H), 7.06-6.82 (m, 2H), 3.86 (s, 2H),1.29 (s, 6H).

Intermediate 88. 1-tert-butyl 2-methyl 5-bromoindoline-1,2-dicarboxylate

NBS (128 mg, 0.721 mmol) was added to a solution of 1-tert-butyl2-methyl indoline-1,2-dicarboxylate (200 mg, 0.721 mmol) in DMF (1 mL)at 0° C. The mixture was stirred at rt for 3 d, then was diluted withwater and extracted with EtOAc. The organic phase was concentrated andthe residue was purified by flash chromatography (0-100° % EtOAc/hexanesgradient) to afford Intermediate 88 (175 mg, 68% yield) as a colorlessoil. MS(ESI) m/z: 300.0 (M−/−Bu+2H)⁺; ¹H NMR (400 MHz, chloroform-d) δ7.81-7.70 (m, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.22 (s, 1H), 4.86 (d, J=7.9Hz, 1H), 3.75 (s, 3H), 3.48 (dd, J=16.7, 11.4 Hz, 1H), 3.09 (dd, J=16.7,4.4 Hz, 1H), 1.65-1.41 (m, 9H).

Intermediate 89: ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate

Intermediate 89A: ethyl 2-chloro-3-hydroxyacrylate

To a cooled (ice-water) suspension of KO^(t)Bu (10.5 g, 94 mmol) indiisopropylether (150 mL) were added ethyl 2-chloroacetate (10.0 mL, 94mmol) and ethyl formate (7.55 mL, 94 mmol). The reaction was stirredunder N₂ at rt overnight. The solid formed was collected by filtration,and then was washed with diethyl ether. The solid was redissolved in H₂O(100 mL), and the aqueous solution was washed with diethyl ether (50mL). The aqueous solution was then cooled to 0° C., and it was acidifiedto pH ˜5 with 1.0 N HCl. It was extracted with ether (2×60 mL). Thecombined organic phase was dried over MgSO₄, filtered and the solventwas removed to give a beige liquid (7.03 g, 50%) as the product.

Intermediate 89

A solution of 2-aminopyridin-4-ol (0.50 g, 4.54 mmol) and Intermediate89A (1.03 g, 6.81 mmol) in EtOH (10 mL) was stirred under N₂ at refluxfor 4 h. The solvent was removed. The crude product was purified bynormal phase chromatography to provide Intermediate 89 (0.55 g, 60%) asa light tan solid. ¹H NMR (500 MHz, CD₃OD) δ 9.35 (d, J=7.4 Hz, 1H),8.49 (s, 1H), 7.21-7.11 (m, 2H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2Hz, 3H). LC-MS(ESI) m/z: 207.1 [M+H]⁺.

The following intermediates were prepared by following a similarprocedure to that described in Intermediate 89 by reacting Intermediate89A with the appropriate aminopyridine derivatives.

Intermediate 90: ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.42 (dd, J=7.3, 0.9 Hz, 1H), 8.43 (s, 1H),8.16-8.08 (m, 1H), 7.18 (dd, J=7.0, 1.5 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H),1.44 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 216.0 [M+H]⁺.

Intermediate 91: ethyl 8-cyanoimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.54 (dd, J=7.0, 1.1 Hz, 1H), 8.39 (s, 1H),7.85 (dd, J=7.2, 1.2 Hz, 1H), 7.14 (t, J=7.0 Hz, 1H), 4.45 (q, J=7.3 Hz,2H), 1.44 (t, J=7.0 Hz, 3H). LC-MS(ESI) m/z: 216.0 [M+H]⁺.

Intermediate 92: ethyl8-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.50 (d, J=6.8 Hz, 1H), 8.38 (s, 1H), 7.76 (d,J=7.3 Hz, 1H), 7.12 (t, J=7.0 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t,J=7.2 Hz, 3H). LC-MS(ESI) m/z: 259.0 [M+H]⁺.

Intermediate 93: ethyl 8-chloroimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.26 (dd, J=7.0, 0.9 Hz, 1H), 8.32 (s, 1H),7.49 (dd, J=7.5, 0.9 Hz, 1H), 6.99 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.2 Hz,2H), 1.43 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 225.0/227.0 [M+H]⁺.

Intermediate 94: ethyl 7-phenylimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.33 (dd, J=7.2, 0.8 Hz, 1H), 8.32 (s, 1H),7.93 (d, J=0.9 Hz, 1H), 7.72-7.66 (m, 2H), 7.54-7.48 (m, 2H), 7.47-7.41(m, 1H), 7.33 (dd, J=7.2, 1.9 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 1.44 (t,J=7.2 Hz, 3H). LC-MS(ESI) m/z: 267.0 [M+H]⁺.

Intermediate 95: ethyl 7-methylimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.09 (d, J=7.5 Hz, 1H), 8.17 (s, 1H), 6.99 (d,J=2.4 Hz, 1H), 6.72 (dd, J=7.7, 2.6 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H),3.90 (s, 3H), 1.40 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 221.0 [M+H]⁺.

Intermediate 96: ethyl8-chloro-7-methylimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.36 (s, 1H), 8.23 (s, 1H), 7.57 (s, 1H), 4.41(q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z:239.0 [M+H]⁺.

Intermediate 97: ethyl 8-(benzyloxy)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J=6.8 Hz, 1H), 8.25 (s, 1H), 7.49 (d,J=7.0 Hz, 2H), 7.42-7.28 (m, 3H), 6.87 (t, J=7.4 Hz, 1H), 6.73 (d, J=7.7Hz, 1H), 5.36 (s, 2H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).LC-MS(ESI) m/z: 297.0 [M+H]⁺.

Intermediate 98: ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.36-9.23 (m, 1H), 8.26 (s, 1H), 7.43-7.30 (m,1H), 6.91 (td, J=7.3, 2.5 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t,J=7.0 Hz, 3H). LC-MS(ESI) m/z; 209.0 [M+H]⁺.

Intermediate 99: ethyl7-(methylthio)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.09 (dd, J=7.3, 0.7 Hz, 1H), 8.21 (s, 1H),7.37 (d, J=1.3 Hz, 1H), 6.88 (dd, J=7.3, 2.0 Hz, 1H), 4.40 (q, J=7.1 Hz,2H), 2.56 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 237.1 [M+H]⁺.

Intermediate 100: ethyl 7-(benzloxy)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.12 (d, J=7.7 Hz, 1H), 8.17 (s, 1H),7.49-7.34 (m, 5H), 7.06 (d, J=2.4 Hz, 1H), 6.79 (dd, J=7.6, 2.5 Hz, 1H),5.14 (s, 2H), 4.39 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LC-MS(ESI)m/z: 297.0 [M+H]⁺.

Intermediate 101: 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylicacid

A solution of 4-(trifluoromethyl)pyridin-2-amine (100 mg, 0.62 mmol) andethyl 2-chloro-3-hydroxyacrylate (139 mg, 0.93 mmol) in EtOH (3 mL) in asealed vial was stirred under N₂ at 80° C., overnight. The reaction wascooled to it. To the reaction were added water (0.5 mL) and LiOH (57.0mg, 2.34 mmol). It was stirred at 60° C. for 3 h. The solvent wasremoved. The crude product was purified by reverse phase chromatographyto provide Intermediate 101 (132 mg, 93% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.43 (d, J=7.3 Hz, 1H), 8.42 (s, 1H), 8.32-8.22 (m,1H), 7.49 (dd, J=7.4, 1.9 Hz, 1H). LC-MS(ESI) m/z: 230.9 [M+H]⁺.

The following intermediates were prepared by following a similarprocedure to that described in Intermediate 101 by reacting Intermediate88A with the appropriate aminopyridine derivatives.

Intermediate 102:8-fluoro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.39 (s, 1H), 7.94 (dd,J=10.6, 1.3 Hz, 1H). LC-MS(ESI) m/z: 248.9 [M+H]⁺.

Intermediate 103: 6-fluoro-8-methylimidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (ddd, J=4.6, 2.4, 0.7 Hz, 1H), 8.32 (s,1H), 7.64-7.55 (m, 1H), 2.59 (s, 3H). LC-MS(ESI) m/z: 195.0 [M+H]⁺.

Intermediate 104: 6,8-difluoroimidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (br s, 1H), 9.15 (ddd, J=4.4, 2.0, 0.9Hz, 1H), 8.29 (s, 1H), 7.87 (ddd, J=11.1, 9.1, 2.2 Hz, 1H). LC-MS(ESI)m/z: 199.0 [M+H]⁺.

Intermediate 105: 6-fluoro-5-methylimidazo[1,2-a]pyridine-3-carboxylicacid

LC-MS(ESI) m/z: 195.0 [M+H]⁺.

Intermediate 106: 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (ddd, J=4.8, 2.5, 0.7 Hz, 1H), 8.34 (s,1H), 7.90 (ddd, J=9.9, 5.3, 0.7 Hz, 1H), 7.71 (ddd, J=9.9, 8.1, 2.6 Hz,1H). LC-MS(ESI) m/z: 180.9 [M+H]⁺.

Intermediate 107: 6-fluoro-7-methylimidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.81(d, J=7.0 Hz, 1H), 2.42 (s, 3H). LC-MS(ESI) m/z: 195.0 [M+H]⁺.

Intermediate 108: 7-methylimidazo[,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (d, J=7.0 Hz, 1H), 8.41 (s, 1H), 7.68(s, 1H), 7.24 (dd, J=7.0, 1.5 Hz, 1H), 2.48 (s, 3H). LC-MS(ESI) m/z:177.0 [M+H]⁺.

Intermediate 109 methyl4-morpholinopyrazolo[1:5-a]pyridine-3-carboxylate

Methyl 4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.39 mmol),Pd(OAc)₂ (5.3 mg, 0.024 mmol), BINAP (22 mg, 0.035 mmol) and Cs₂CO₃ (192mg, 0.59 mmol) were placed in a pressure vial. The reaction mixture wasdegassed (3× vacuum and argon), then toluene (2 mL) and morpholine(0.044 mL, 0.51 mmol) were added. The reaction mixture was degassedagain, and then was stirred at 120° C. for 3 h. After cooled to rt, thereaction was filtered through a pad of CELITE®, and the solvent wasremoved. The crude product was purified by reverse phase chromatographyto provide Intermediate 109 (74 mg, 72%) as a light tan solid. ¹H NMR(400 MHz, CDC₃) δ 8.46 (s, 1H), 8.43 (d, J=6.6 Hz, 1H), 7.31 (d, J=7.7Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 4.11-4.04 (m, 4H), 3.94 (s, 3H),3.40-3.27 (m, 4H). LC-MS(ESI) m/z: 262.0 [M+H]⁺.

Intermediate 110: 4-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

To a solution of Intermediate 109 (63 mg, 0.24 mmol) in THF (2 mL) andH₂O (1 mL) was added LiOH (29 mg, 1.21 mmol) at rt. The reaction wasstirred under N₂ at rt for 2 days. The solvent was removed to give awhite solid a crude product (85 mg). LC-MS(ESI) m/z: 248.0 [M+H]⁺.

Intermediate 111: ethyl7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-carboxylate

To a solution of ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (55mg, 0.27 mmol) in DMF (2 mL) were added sodium2-chloro-2,2-difluoroacetate (81 mg, 0.53 mmol), K₂CO₃ (74 mg, 0.53mmol) and H₂O (0.4 mL) at rt. The reaction was stirred under N₂ at 110°C. for 2 h. The solvent was removed. The crude product was purified bynormal phase chromatography to provide Intermediate 111 (21 mg, 31%) asa white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.27 (d, J=7.5 Hz, 1H), 8.26 (s, 1H), 7.37 (d,J=2.4 Hz, 1H), 6.88 (dd, J=7.5, 2.4 Hz, 1H), 6.65 (t, J=72.6 Hz, 1H),4.41 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 257.0[M+H]⁺.

The following compounds were prepared by following similar procedure tothose described in the synthesis of Intermediate 109 and Intermediate110.

Intermediate 112: 7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (dd, J=7.5, 0.7 Hz, 1H), 8.31 (s, 1H),7.56 (d, J=2.0 Hz, 1H), 7.43 (t, J=73.1 Hz, 1H), 7.18 (dd, J=7.7, 2.6Hz, 1H). LC-MS(ESI) m/z; 229.0 [M+H]⁺.

Intermediate 113: 8-(benzyloxy)imidazo[1,2-a]pyridine-3-carboxylic acid

LC-MS(ESI) m/z: 269.0 [M+H]⁺.

Intermediate 114: ethyl 7-morpholinoimidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J=7.7 Hz, 1H), 8.14 (s, 1H), 6.86 (d,J=2.4 Hz, 1H), 6.74 (dd, J=7.7, 2.6 Hz, 1H), 4.36 (q, J=7.0 Hz, 2H),3.93-3.75 (m, 4H), 3.33-3.16 (m, 4H), 1.39 (t, J=7.2 Hz, 3H). LC-MS(ESI)m/z: 276.1 [M+H]⁺.

Intermediate 115: ethyl7-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.05 (d, J=7.7 Hz, 1H), 8.14 (s, 1H), 6.90 (d,1=2.6 Hz, 1H), 6.75 (dd, J=7.7, 2.6 Hz, 1H), 4.37 (q, J=7.3 Hz, 2H),3.56-3.44 (m, 4H), 2.21-2.04 (m, 4H), 1.39 (t, J=7.2 Hz, 3H). LC-MS(ESI)m/z: 310.0 [M+H]⁺.

Intermediate 116: ethyl7-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J=7.7 Hz, 1H), 8.14 (s, 1H), 6.55 (d,J=2.4 Hz, 1H), 6.46 (dd, J=7.6, 2.5 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H),3.76 (t, J=12.9 Hz, 2H), 3.64 (t, J=7.3 Hz, 2H), 2.67-2.45 (m, 2H), 1.39(t, J=7.0 Hz, 3H). LC-MS(ESI) m/z: 296.0 [M+H]⁺.

Intermediate 117: (R)-ethyl7-(3-fluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.03 (d, J=7.5 Hz, 1H), 8.12 (s, 1H), 6.55 (d,J=2.4 Hz, 1H), 6.50 (dd, J=7.7, 2.4 Hz, 1H), 5.53-5.31 (m, 1H), 4.36 (q,J=7.1 Hz, 2H), 3.69 (d, J=1.8 Hz, 1H), 3.64-3.53 (m, 3H), 2.53-2.37 (m,1H), 2.33-2.08 (m, 1H), 1.39 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 278.0[M+H]⁺.

Intermediate 118: (S)-ethyl7-(3-fluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.03 (d, J=7.5 Hz, 1H), 8.12 (s, 1H), 6.55 (d,J=2.4 Hz, 1H), 6.50 (dd, J=7.6, 2.5 Hz, 1H), 5.52-5.32 (m, 1H), 4.36 (q,J=7.0 Hz, 2H), 3.69 (d, J=2.0 Hz, 1H), 3.63-3.54 (m, 3H), 2.52-2.36 (m,1H), 2.33-2.08 (m, 1H), 1.39 (t, J=7.0 Hz, 3H). LC-MS(ESI) m/z: 278.0[M+H]⁺.

Intermediate 119: methyl7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J=7.7 Hz, 1H), 8.13 (s, 1H), 6.87 (d,J=2.4 Hz, 1H), 6.76 (dd, J=7.8, 2.3 Hz, 1H), 3.89 (s, 3H), 3.42-3.27 (m,4H), 2.63-2.52 (m, 4H), 2.36 (s, 3H). LC-MS(ESI) m/z: 275.0 [M+H]⁺.

Intermediate 120: (R)-ethyl7-(3-hydroxypyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J=7.5 Hz, 1H), 8.07 (s, 1H), 6.43 (d,J=2.2 Hz, 1H), 6.40 (dd, J=7.6, 2.5 Hz, 1H), 4.68-4.60 (m, 1H), 4.36 (q,J=7.1 Hz, 2H), 3.62-3.50 (m, 2H), 3.47-3.35 (m, 2H), 2.25-2.09 (m, 2H),1.39 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 276. I[M+H]⁺.

Intermediate 121:7-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (d, J=7.9 Hz, 1H), 8.45 (s, 1H), 7.40(dd, J=7.9, 2.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 3.76-3.57 (m, 4H),2.22-1.93 (m, 4H). LC-MS(ESI) m/z: 282.0 [M+H]⁺.

Intermediate 122:7-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (d, J=7.7 Hz, 1H), 8.45 (s, 1H), 7.05(dd, J=7.8, 2.5 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 3.97 (t, J=13.0 Hz,2H), 3.72 (t, J=7.3 Hz, 2H), 2.63 (tt, J=14.3, 7.4 Hz, 2H). LC-MS(ESI)m/z: 268.0 [M+H]⁺.

Intermediate 123:(R)-7-(3-fluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=7.7 Hz, 1H), 8.45 (s, 1H), 7.05(dd, J=7.7, 2.4 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 5.71-5.38 (m, 1H), 3.78(s, 1H), 3.68 (t, J=10.2 Hz, 1H), 3.58-3.51 (m, 2H), 2.42-2.12 (m, 2H).LC-MS(ESI) m/z: 250.0 [M+H]⁺.

Intermediate 124:(S)-7-(3-fluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=7.7 Hz, 1H), 8.45 (s, 1H), 7.05(dd, J=7.7, 2.4 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 5.65-5.39 (m, 1H),3.83-3.73 (m, 1H), 3.72-3.54 (m, 3H), 2.42-2.11 (m, 2H). LC-MS(ESI) m/z:250.0 [M+H]J.

Intermediate 125:(R)-7-(3-hydroxpyrrolidin-1-yl)imidazo[,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=7.7 Hz, 1H), 8.48 (s, 1H), 7.05(dd, J=7.8, 2.3 Hz, 1H), 6.50 (d, J=2.2 Hz, 1H), 4.47 (br. s., 1H),3.65-3.50 (m, 4H), 2.17-2.03 (m, 1H), 2.03-1.93 (m, 1H). LC-MS(ESI) m/z:248.1 [M+H]⁺.

Intermediate 126: 7-(methylthio)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, CD₃OD) δ 9.36 (dd, J=7.4, 0.6 Hz, 1H), 8.43 (s, 1H),7.55 (d, J=1.5 Hz, 1H), 7.40 (dd, J=7.3, 2.0 Hz, 1H), 2.68 (s, 3H).LC-MS(ESI) m/z: 209.0 [M+H]⁺.

Intermediate 127:7-((2-hydroxyethyl)(methyl)amino)imidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (d, J=7.9 Hz, 1H), 8.44 (s, 1H), 7.21(dd, J=7.9, 2.6 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 3.62 (t, J=3.6 Hz, 4H),3.12 (s, 3H). LC-MS(ESI) m/z: 236.0 [M+H]⁺.

Intermediate 128:7-((2-methoxyethyl)(methyl)amino)imidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (d, J=7.9 Hz, 1H), 8.42 (s, 1H), 7.21(dd, J=8.0, 2.5 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 3.77-3.69 (m, 2H), 3.56(t, J=5.3 Hz, 2H), 3.25 (s, 3H), 3.11 (s, 3H). LC-MS(ESI) m/z: 250.0[M+H]⁺.

Intermediate 129:7-((2-hydroxy-2-methylpropyl)(methyl)amino)imidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J=8.1 Hz, 1H), 8.44 (s, 1H), 7.32(d, J=7.9 Hz, 1H), 6.71 (br. s., 1H), 4.66 (br. s., 1H), 3.52 (s, 2H),3.16 (s, 3H), 1.15 (s, 6H). LC-MS(ESI) m/z: 264.1 [M+H]⁺.

Intermediate 130: ethyl7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.37 mmol),allylpalladium chloride dimer (2.0 mg, 5.6 μmol), RockPhos (5.2 mg,0.011 mmol) and Cs₂CO₃ (182 mg, 0.56 mmol) were placed in a pressurevial. The reaction mixture was degassed (3× vacuum and argon), thentoluene (2 mL) and 2-morpholinoethanol (73 mg, 0.56 mmol) were added.The reaction mixture was degassed again, and was stirred at 90° C. for 5h. After cooled to rt, the solvent was removed. The crude product waspurified by reverse phase chromatography to provide Intermediate 130 (96mg, 81%) as a light tan solid. LC-MS(ESI) m z: 320.0 [M+H]⁺.

The following compounds were prepared by following similar procedures tothose described in the synthesis of Intermediate 110, Intermediate 111and Intermediate 130.

Intermediate 131:7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (d, J=7.7 Hz, 1H), 8.42 (s, 1H), 7.40(d, J=2.4 Hz, 1H), 7.12 (dd, J=7.6, 2.5 Hz, 1H), 4.60-4.54 (m, 2H),3.68-3.64 (m, 2H), 3.59-3.17 (br, m, 8H). LC-MS(ESI) m/z: 292.0 [M+H]⁺.

Intermediate 132:7-(2-(pyrrolidin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (d, J=7.5 Hz, 1H), 7.33 (d, J=2.4 Hz,1H), 7.07 (d, J=1.8 Hz, 1H), 7.02 (dd, J=7.6, 2.5 Hz, 1H), 4.54-4.36 (m,2H), 3.86-2.93 (m, 6H), 2.06 (d, J=9.0 Hz, 2H), 1.95-1.75 (m, 2H).LC-MS(ESI) m/z: 276.0 [M+H]⁺.

Intermediate 133:7-((2-hydroxy-2-methylpropyl)amino)imidazo[1,2-a]pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 7.68(br. s., 1H), 7.11 (dd, J=7.7, 2.4 Hz, 1H), 6.66 (br. s., 1H), 3.12 (d,J=5.7 Hz, 2H), 1.18 (s, 6H). LC-MS(ESI) m/z: 250.0 [M+H]⁺.

Intermediate 134:7-(2-hydroxy-2-methylpropoxy)imidazo[1,2-a]pyridine-3-carboxylic acid,and Intermediate 135:1-(2-hydroxy-2-methylpropyl)-7-oxo-1,7-dihydroimidazo[1,2-a]pyridine-3-carboxylicacid

To a solution of ethyl 7-hydroxyimidazo[1,2-a]pyridine-2-carboxylate(100 mg, 0.46 mmol) in acetonitrile (3 mL) and H₂O (0.2 mL) were addedK₂CO₃ (268 mg, 1.94 mmol) and 2,2-dimethyloxirane (0.66 mL, 7.27 mmol)at it. The reaction was heated with microwave at 120° C. for 30 min. Thesolvent was removed. The residue were added THF (2 mL), H₂O (0.5 mL) andLiOH (20 mg). After stirring at 50° C. for 5 h, the solvent was removed.Purification by reverse phase chromatography gave Intermediate 134 (55mg, 45%) and Intermediate 135 (23 mg, 13%). Intermediate 134: ¹H NMR(500 MHz. DMSO-d₆) δ 9.20 (d, J=7.7 Hz, 1H), 8.44 (s, 1H), 7.28 (d,J=2.5 Hz, 1H), 7.15 (dd, J=7.7, 2.5 Hz, 1H), 3.94 (s, 2H), 1.24 (s, 6H).LC-MS(ESI) m/z: 251.0 [M+H]⁺. Intermediate 135: ¹H NMR (500 MHz,DMSO-d₆) δ 9.30 (d, J=7.7 Hz, 1H), 8.56 (s, 1H), 7.49 (d, J=2.2 Hz, 1H),7.24 (dd, J=7.7, 2.5 Hz, 1H), 4.24 (s, 2H), 1.16 (s, 6H). LC-MS(ESI)m/z: 251.0 [M+H]⁺.

Intermediate 136: ethyl7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylate

To a solution of ethyl 7-bromo-1H-indole-2-carboxylate (100 mg, 0.37mmol) in dioxane (3 mL) and H₁-120 (0.5 mL) were added1-methyl-4-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (93mg, 0.45 mmol), K₃PO₄ (198 mg, 0.93 mmol) and XPhos-G2-Pd-preCat (14.7mg, 0.019 mmol) at it. The reaction was stirred under N₂ at 100° C. for1 h. The reaction was cooled to t. The solvent was removed. Purificationby normal phase chromatography provided Intermediate 136 (94 mg, 94%) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (br. s., 1H), 7.82 (s,1H), 7.69 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.3, 1.1 Hz, 1H),7.27 (d, J=2.2 Hz, 1H), 7.18 (dd, J=7.9, 7.3 Hz, 1H), 4.41 (q, J=7.2 Hz,2H), 4.03 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 270.1 [M+H]⁺.

Intermediate 137: 7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-2-carboxylicacid

LC-MS(ESI) m/z: 242.1 [M+H]⁺.

Intermediate 138: ethyl4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

NaOH (3.53 g, 88 mmol) was added to a solution of diethyl1H-pyrazole-3,5-dicarboxylate (5.35 g, 25.2 mmol) in acetonitrile (40mL). After 30 min, 2-chloroethanamine hydrochloride (3.22 g, 27.7 mmol)and tetrabutylammonium hydrogen sulfate (0.43 g, 1.26 mmol) were added.The mixture was refluxed for 20 h. After cooled, conc. HCl (5 mL) wasadded. The mixture was extracted with CH₂Cl₂, washed with brine. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. Normal phase chromatography afforded Intermediate 138(2.72 g, 52%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (br s,1H), 7.07 (s, 1H), 4.40 (dd, J=6.7, 5.5 Hz, 2H), 4.27 (q, J=7.2 Hz, 2H),3.68-3.61 (m, 2H), 1.28 (t, J=7.0 Hz, 3H). LC-MS(ESI) m/z: 210.1 [M+H]⁺.

Intermediate 139:4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid

A solution of lithium hydroxide monohydrate (2.73 g, 65.0 mmol) in H₂O(30.0 mL) was added to a suspension of ethyl4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (2.72 g,13.0 mmol) in THF (30 mL) and MeOH (30 mL) at 0° C. Then, the suspensionwas stirred at rt overnight. The solvents were removed. H₂O (20 mL) wasadded. The clear solution was cooled to 0° C., cone. HCl (5.42 mL, 65.0mmol) was added to bring pH to ˜3. The suspension was stirred at 0° C.for 2 h, filtered, and dried to give a white solid (2.2 g, 93%).LC-MS(ESI) m/z: 182.1 [M+H]⁺.

Intermediate 140: ethyl3-(prop-1-en-2-yl)imidazo[1,5-a]pyridine-1-carboxylate

To a solution of ethyl 3-bromoimidazo[1,5-a]pyridine-1-carboxylate (30mg, 0.11 mmol) in dioxane (2 mL) and H₂O (0.5 mL) were added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (28 mg, 0.17mmol), K₃PO₄ (59 mg, 0.28 mmol) and PdCl₂(dppf) (8.2 mg, 0.011 mmol) atrt. The reaction was heated with microwave at 120° C. for 15 min. Theorganic phase was separated, and the solvent was removed. The crudeproduct was purified by normal phase chromatography to provide ethyl3-(prop-1-en-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (21 mg, 82%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (dd, r=7.3, 1.1 Hz, 1H),8.24 (dt, J=9.1, 1.3 Hz, 1H), 7.12 (ddd, J=9.1, 6.5, 0.9 Hz, 1H),6.84-6.75 (m, 1H), 5.70-5.60 (m, 1H), 5.53 (s, 1H), 4.50 (q, J=7.2 Hz,2H), 2.41-2.34 (m, 3H), 1.48 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 231.0[M+H]⁺.

Intermediate 141: ethyl3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate

To a solution of ethyl3-(prop-1-en-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (21 mg, 0.091mmol) in MeOH (3 mL) was added catalytic amount of 10% Pd/C. Thereaction was stirred under a hydrogen balloon at rt for 1 h. Thereaction was filtered through a pad of CELITE®, and the solvent wasremoved to give a white solid. (20 mg, 93%) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 4.35 (q, J=7.1 Hz, 2H), 3.88 (t, J=6.1 Hz, 2H), 3.08(t, J=6.5 Hz, 2H), 2.97 (spt, J=6.9 Hz, 1H), 2.02-1.92 (m, 2H),1.88-1.78 (m, 2H), 1.40-1.31 (m, 9H). LC-MS(ESI) m/z: 237.1 [M+H]⁺.

Intermediate 142: ethyl [1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

To a solution of 2-hydrazinylpyridine (1.3 g, 11.9 mmol) in toluene (10mL) were added DIEA (6.2 mL, 35.7 mmol) and ethyl 2-chloro-2-oxoacetate(1.63 g, 11.9 mmol) at 0° C. The reaction was stirred under N₂ at 0° C.for 10 min. To the reaction was then added T3P® (50% in EtOAc, 8.5 mL,14.3 mmol) and the reaction was heated at 110° C. for 5 h. After cooledto rt, the reaction mixture was diluted with EtOAc, washed with 1M HCl,saturated NaHCO₃ and brine. The organic phase was dried over Na₂SO₄,filtered and concentrated. Purification by normal phase chromatographyprovided Intermediate 142 (0.36 g, 16%) as a light brown solid. ¹H NMR(400 MHz, CDCl₃) δ 9.13 (d, J=7.0 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.46(ddd, J=9.2, 6.8, 1.0 Hz, 1H), 7.15-7.05 (m, 1H), 4.54 (q, J=7.3 Hz,2H), 1.47 (t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 191.9 [M+H]⁺.

Intermediate 143: 3-methoxy-4-(1H-pyrazol-4-yl)benzoic acid

Intermediate 143A: methyl 3-methoxy-4-(1H-pyrazol-4-yl)benzoate

To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) indioxane (30 mL) and water (5 mL) were added ter-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) andPdCl₂(dppf) (0.197 g, 0.269 mmol) at it. The reaction was stirred underargon at 100° C. for 3 hrs. The reaction mixture was diluted with EtOAc,washed with H₂O. The organic phase was dried over sodium sulfate,filtered and concentrated. The residue was dissolved in DCM (10 mL) andTFA (5 mL) was added. The reaction was stirred at rt for 1.5 hrs.Solvent was removed. The residue was taken into EtOAc, which was washedwith NaHCO₃ (3×) and brine, dried over NaSO₄, filtered and concentrated.The crude product was purified by normal phase chromatography. Desiredproduct was isolated as white solid (0.86 g, 69% yield). LCMS(ESI) m/z:233.0 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 2H), 7.73-7.66 (m, 1H),7.66-7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).

Intermediate 143

To a solution of Intermediate 143A (860 mg, 3.70 mmol) in THF (10 mL)and water (5 mL) was added LiOH (133 mg, 5.55 mmol) at RT. The reactionwas stirred under argon at RT for 5 hrs. The reaction was neutralizedwith 1 N HCl solution. Solvent was removed to give pale solid ofIntermediate 143 (810 mg, 100% yield), which was used without furtherpurification. LCMS(ESI) m/z: 219.0 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.91 (br. s, 2H), 7.54 (br. s, 1H), 7.43 (br. s, 2H), 3.84 (s, 3H).

Intermediate 144: 3-cyano-4-(1H-pyrazol-4-yl)benzoic acid

Intermediate 144A: methyl 4-bromo-3-cyanobenzoate

To a solution of methyl 4-bromo-3-methylbenzoate (1.2 g, 5.0 mmol) inacetonitrile (5 mL) were added 2-hydroxyisoindoline-1,3-dione (0.82 g,5.0 mmol), Pd(OAc)₂ (56 mg, 0.25 mmol) and tert-butyl nitrite (1.8 mL,15 mmol) at rt. The reaction was stirred under argon at 80° C. for 24 h,and then was cooled to rt. The reaction mixture was diluted with EtOAc,washed with H₂O and brine. The organic phase was dried over sodiumsulfate, filtered and concentrated. The crude product was purified bynormal phase chromatography to give Intermediate 144A (0.65 g, 54%) aswhite solid. LC-MS(ESI) m/z: 249.9/241.9 [M+H]⁺: ¹H NMR (400 MHz, CDCl₃)δ 8.31 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 3.96 (s, 3H).

Intermediate 144B: methyl 3-cyano-4-(1H-pyrazol-4-yl)benzoate

To a solution of Intermediate 144A (0.25 g, 1.0 mmol) in dioxane (10 mL)were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.37 g, 1.3 mmol), K₃PO₄ (1 M, 3.1 mL, 3.1 mmol) and XPhos-G2-Pd-PreCat(16 mg, 0.021 mmol) at rt. The reaction was stirred under argon at 90°C. for 2 h. The reaction was cooled to ft. The reaction mixture wasdiluted with EtOAc, washed with H₂O and brine. The organic phase wasdried over sodium sulfate, filtered and concentrated. The crude productwas purified by normal phase chromatography to give Intermediate 144B(0.22 g, 93%) as white solid. LC-MS(ESI) m/z: 228.1 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ 11.27 (br s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.27-8.17 (m,3H), 7.70 (d, J=8.1 Hz, 1H), 3.97 (s, 3H).

Intermediate 144

To a solution of Intermediate 144B (0.22 g, 0.97 mmol) in THF (7 mL) andwater (3 mL) was added LiOH (70 mg, 2.9 mmol) at t. The reaction wasstirred under argon at rt for 5 h. The reaction was neutralized with 1.0N HCl. The solvent was removed to give Intermediate 144 (0.21 g, 100%)as white solid. LC-MS(ESI) m/z: 214.1 [M+H]⁺: ¹H NMR (400 MHz, DMSO-d₆)δ 8.02 (d, J=1.5 Hz, 1H), 7.95-7.87 (m, 3H), 7.47 (d, J=8.1 Hz, 1H).

Intermediate 145: 3-methyl-4-(H-pyrazol-4-yl)benzoic acid

Intermediate 145A: tert-butyl4-(4-(methoxycarbonyl)-2-methylphenyl)-1H-pyrazole-1-carboxylate, andIntermediate 145B: methyl 3-methyl-4-(1H-pyrazol-4-yl)benzoate

To a solution of methyl 4-bromo-3-methylbenzoate (1.1 g, 4.8 mmol) indioxane (20 mL) and water (5 mL) were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(1.6 g, 5.3 mmol), potassium phosphate (2.6 g, 12 mmol) and PdCl₂(dppf)(0.18 g, 0.24 mmol) at rt. The reaction was stirred under argon at 90°C. for 3 h. The reaction mixture was diluted with EtOAc, washed with H₂Oand brine. The organic phase was dried over sodium sulfate, filtered andconcentrated. The crude product was purified by normal phasechromatography to give Intermediate 145A (1.1 g, 70%) and Intermediate145B (0.28 g, 27%) as white solids. Intermediate 145A: LCMS(ESI) m/z:317.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.95 (d, J=0.4 Hz,1H), 7.92-7.85 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.45 (s,3H), 1.69 (s, 9H). Intermediate 145B: LCMS(ESI) m/z: 217.1, (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 11.03 (br s, 1H), 7.97-7.92 (m, 1H), 7.90-7.85(m, 1H), 7.80 (s, 2H), 7.43 (d, J=7.9 Hz, 1H), 3.93 (s, 3H), 2.47 (s,3H).

Intermediate 145

To a solution of a mixture of Intermediate 145A and Intermediate 145B(4.7 mmol) in THF (15 mL) and water (5 mL) was added LiOH (0.34 g, 14mmol) at it. The reaction was stirred under argon at rt overnight. Thesolvent was removed under reduced pressure and the crude product wasdried to give Intermediate 145 (0.95 g, 100%) as a light tan solid.LCMS(ESI) m/z: 203.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (s, 1H),7.60 (br s, 3H), 7.26 (d, J=7.9 Hz, 1H), 2.37 (s, 3H).

Intermediate 146: 2-methoxy-4-(1H-pyrazol-4-yl)benzoic acid

Intermediate 146 was synthesized by following a similar route toIntermediate 143 using methyl 4-bromo-2-methoxybenzoate in stepIntermediate 143A. LCMS(ESI) m/z; 219.1 (M+H)⁺.

Intermediate 147: 6H-isochromeno[3,4-c]pyridine-8-carboxylic acid

Intermediate 147A: methyl 4-bromo-3-(hydroxymethyl)benzoate

To a solution of methyl 4-bromo-3-formylbenzoate (1.53 g, 6.29 mmol) inMeOH (20 mL) was added NaBH₄ (0.238 g, 6.29 mmol) at 0° C. The reactionwas stirred under argon at 0° C. for 30 min. LCMS showed the reactionwas completed. The reaction mixture was diluted with EtOAc, washed withH₂O and brine. The organic phase was dried over sodium sulfate, filteredand concentrated to give Intermediate 147A as a clear colorless oil(1.50 g, 97%). LCMS(ESI) m/z: 244.9/246.9 [M+H]*; ¹H NMR (400 MHz,CDCl₃) δ 8.17 (d, J=2.0 Hz, 1H), 7.82 (dd, J=8.4, 2.2 Hz, 1H), 7.62 (d,J=8.4 Hz, 1H), 4.79 (s, 2H), 3.93 (s, 3H).

Intermediate 147B: methyl4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)benzoate

To a solution of Intermediate 147A (1.49 g, 6.08 mmol) in DMF (10 mL)were added imidazole (0.621 g, 9.12 mmol) and TBS-Cl (1.10 g, 7.30 mmol)at 0° C. The reaction was stirred under argon at rt overnight. Thereaction mixture was diluted with EtOAc, washed with H₂O and brine. Theorganic phase was dried over sodium sulfate, filtered and concentrated.The crude product was purified by normal phase chromatography to giveIntermediate 147B (1.89 g, 87%). LCMS(ESI) m/z: 359.0/360.9 [M+H]; ¹HNMR (400 MHz, CDCl₃) δ 8.26-8.21 (m, 1H), 7.79 (dd, J=8.4, 2.2 Hz, 1H),7.58 (d, J=8.1 Hz, 1H), 4.76 (s, 2H), 3.93 (s, 3H), 1.00 (s, 9H), 0.16(s, 6H).

Intermediate 147C: methyl3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of Intermediate 147B (1.41 g, 3.92 mmol) in acetonitrile(15 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.20 g,4.71 mmol), KOAc (0.77 g, 7.85 mmol), and PdCl₂(dppf) (0.14 g, 0.20mmol) at rt. The reaction was stirred under argon at 90° C. for 5 h. Thesolvent was removed. The crude product was purified by normal phasechromatography to afford Intermediate 147C as a clear colorless oil(1.18 g, 74%). LCMS(ESI) m/z: 407.1 [M+H]J; ¹H NMR (400 MHz, CDCl₃) δ8.14 (d, J=0.9 Hz, 1H), 7.79-7.74 (m, 1H), 7.74-7.68 (m, 1H), 4.91 (s,2H), 3.81 (s, 3H), 1.24 (s, 12H), 0.86 (s, 9H), 0.00 (s, 6H).

Intermediate 147D: methyl3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5-fluoropyrimidin-4-yl)benzoate

To a solution of Intermediate 147C (285 mg, 0.701 mmol) in dioxane (2mL) were added 4-chloro-5-fluoropyrimidine (93 mg, 0.701 mmol), K₃PO₄(447 mg, 2.10 mmol) and Pd(Ph₃P)₄ (81 mg, 0.070 mmol) at rt. Thereaction was stirred under argon at 90° C. for 3 h. The reaction mixturewas diluted with EtOAc, washed with H₂O and brine. The organic phase wasdried over sodium sulfate, filtered and concentrated. The crude productwas purified by normal phase chromatography to give Intermediate 147D asa clear colorless oil (225 mg, 85%). LCMS(ESI) m/z: 377.1 [M+H]J; ¹H NMR(400 MHz. CDCl₃) δ 9.14 (d, J=2.9 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.33(d, J=1.1 Hz, 1H), 8.09 (dd, J=7.9, 1.8 Hz, 1H), 7.55 (dd, J=8.0, 1.4Hz, 1H), 4.87 (s, 2H), 3.99 (s, 3H), 0.85 (s, 9H), 0.00 (s, 6H).

Intermediate 147E: methyl 6H-isochromeno[4,3-d]pyrimidine-8-carboxylate

To a solution of Intermediate 147D (225 mg, 0.598 mmol) in THF (3 mL)was added TBAF (1 M in THF, 3.0 mL, 3.0 mmol) at rt. The reaction wasstirred under argon at rt for 30 min. LCMS showed the reaction wascompleted. The solvent was removed. The crude product was purified bynormal phase chromatography to afford Intermediate 147E as a white solid(142 mg, 98%). LCMS(ESI) m/z: 243.1 [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) 8.91(s, 1H), 8.44 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.14 (dd, J=8.0, 1.7 Hz,1H), 7.87 (d, J=0.9 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H).

Intermediate 147

To a solution of Intermediate 147E (142 mg, 0.586 mmol) in THF (6 mL)and H₁-120 (2 mL) was added LiOH (70.2 mg, 2.93 mmol) at RT. Thereaction was stirred under argon at it for 2 h. The solvent was removedto give Intermediate 147 as a white solid (134 mg, 100%). LCMS(ESI) m/z:229.1 [M+H]⁺: ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (s, 1H), 8.46 (s, 1H),8.04 (d, J=8.1 Hz, 1H), 7.95 (d, J=8.1 Hz, H), 7.77 (d, J=1.0 Hz, 1H),5.39 (s, 2H)

Intermediate 148: 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid

To a solution of 4-bromo-3-methoxybenzoic acid (150 mg, 0.65 mmol) indioxane (3 mL) were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(162 mg, 0.78 mmol), K₃PO₄ (413 mg, 1.95 mmol) and XPhos-G2 (26 mg,0.032 mmol) at rt. The reaction was stirred in a sealed vial at 100° C.for 1 h. The solvent was removed. Purification by normal phasechromatography provided Intermediate 148 (88 mg, 58%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (br s, 1H), 8.22 (s, 1H), 7.98(s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.58-7.51 (m, 2H), 3.93 (s, 3H), 3.88(s, 3H). LC-MS(ESI) m/z: 233.0 [M+H]⁺.

Intermediate 149: 3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid

Intermediate 149A: methyl 3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzoate

To a solution of methyl 4-bromo-3-fluorobenzoate (150 mg, 0.64 mmol) indioxane (3 mL) and H₂O (0.5 mL) were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(161 mg, 0.77 mmol), K₃PO₄ (342 mg, 1.61 mmol) and XPhos-G2-Pd-preCat(25 mg, 0.032 mmol) at it. The reaction was heated with microwave at120° C. for 15 min. The reaction was cooled to it and the solvent wasremoved. The crude product was purified by normal phase chromatographyto provide Intermediate 149A (140 mg, 93%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 7.90 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.1, 1.8Hz, 1H), 7.76 (dd, J=11.7, 1.5 Hz, 1H), 7.60 (t, J=1=7.8 Hz, 1H), 3.96(s, 3H), 3.92 (s, 3H). LC-MS(ESI) m/z: 235.0 [M+H]⁺.

Intermediate 149

To a solution of Intermediate 149A (130 mg, 0.56 mmol) in THF (2 mL) andH₂O (0.5 mL) was added LiOH (53.2 mg, 2.22 mmol) at rt. The reaction wasstirred under N₂ at rt for overnight. The reaction was acidified withTFA, and the solvent was removed. The crude product was purified byreverse phase chromatography to provide Intermediate 149 (115 mg, 94%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H), 8.25 (d,J=2.2 Hz, 1H), 7.99 (s, 1H), 7.90-7.80 (m, 1H), 7.76 (dd, J=8.0, 1.7 Hz,1H), 7.70 (dd, J=11.9, 1.5 Hz, 1H), 3.91 (s, 3H). LC-MS(ESI) m/z: 221.0[M+H]⁺.

Intermediate 150: 7-acetylimidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 150A, ethyl 7-acetylimidazo[1,2-a]pyridine-3-carboxylate

Ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (0.100 g, 0.372 mmol),tributyl(1-ethoxyvinyl)stannane (0.20 g, 0.56 mmol), K₂CO₃ (0.103 g,0.74 mmol) and PdCl₂(dppf) (0.027 g, 0.037 mmol) were placed in apressure vial. The reaction mixture was degassed, and toluene (2 mL) wasadded. The reaction mixture was stirred at 120° C. for 5 h. After cooledto rt, it was added HCl to adjust pH to ˜2. The reaction was heated foranother 2 h at 60° C. It was cooled and the solvent was removed. Thecrude product was purified by normal phase chromatography toIntermediate 150A (27 mg, 31%) as a light brown solid. ¹H NMR (400 MHz,CDCl₃) δ 9.34 (d, J=7.3 Hz, 1H), 8.42 (br. s., 1H), 8.32 (s, 1H), 7.61(d, J=7.0 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.69 (s, 3H), 1.47-1.42 (m,3H). LC-MS(ESI) m/z: 233.0 [M+H]⁺.

Intermediate 150

To a solution of Intermediate 150A (27 mg, 0.12 mmol) in THF (2 mL) wereadded LiOH (14 mg, 0.58 mmol) and H₂O (0.5 mL) at rt. The reaction wasstirred under N₂ at it for 3 h. The reaction was acidified with TFA, andthe solvent was removed. Purification by reverse phase chromatographyprovided Intermediate 150 (12 mg, 51%) as a white solid. LC-MS(ESI) m/z:204.9 [M+H]⁺.

Intermediate 151: 3-fluoro-4-(1-(methyl-d₃)-1H-pyrazol-4-yl)benzoic acid

Intermediate 151 A: ter-butyl4-(2-fluoro-4-(methoxycarbonyl)phenyl)-1H-pyrazole-1-carboxylate, andIntermediate 151B: methyl 3-fluoro-4-(1H-pyrazol-4-yl)benzoate

To a solution of methyl 4-bromo-3-fluorobenzoate (526 mg, 2.26 mmol) indioxane (10 mL) and H₂O (2 mL) were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(797 mg, 2.71 mmol), K₃PO₄ (958 mg, 4.51 mmol) and XPhos-G2-Pd-preCat(35.5 mg, 0.045 mmol) at rt. The reaction was stirred under N₂ at 60°C., overnight. The reaction mixture was diluted with EtOAc, washed withH₂O and brine. The organic phase was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by normal phasechromatography to give two products as white solids. Intermediate 151A(463 mg, 64%): ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.5 Hz, 1H), 8.10(s, 1H), 7.84 (dd, J=8.1, 1.5 Hz, 1H), 7.79 (dd, J=11.4, 1.5 Hz, 1H),7.63 (t, J=7.8 Hz, 1H), 3.92 (s, 3H), 1.68 (s, 9H). LC-MS(ESI) m/z;321.0 [M+H]⁺. Intermediate 151B (175 mg, 35%): ¹H NMR (400 MHz, CDCl₃) δ8.06 (d, J=1.8 Hz, 2H), 7.85 (dd, J=8.1, 1.8 Hz, 1H), 7.80 (dd, J=11.7,1.5 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 3.94 (s, 3H). LC-MS(ESI) m/z: 221.0[M+H]⁺.

Alternatively, Intermediate 151B was obtained from Intermediate 15 IA.To a solution of Intermediate 151A (463 mg, 1.45 mmol) in DCM (5 mL) wasadded TFA (2 mL, 26.0 mmol) at rt. The reaction was stirred under N₂ atrt for 2 h. The solvent was removed and the product was dried in vacuoto give a beige solid (480 mg, 99%) as TFA salt. ¹H NMR (400 MHz,DMSO-d₆) δ 8.18 (d, J=2.0 Hz, 2H), 7.92 (t, J=7.9 Hz, 1H), 7.82-7.76 (m,1H), 7.74 (dd, J=11.8, 1.7 Hz, 1H), 3.86 (s, 3H). LC-MS(ESI) m/z: 221.0[M+H]⁺.

Intermediate 151C: methyl3-fluoro-4-(1-(methyl-d₃)-1H-pyrazol-4-yl)benzoate

To a solution of Intermediate 151B (160 mg, 0.73 mmol) in THF (5 mL)were added CD₃OD (26.2 mg, 0.73 mmol). Ph₃P (229 mg, 0.872 mmol) andDIAD (0.18 mL, 0.95 mmol) at rt. The reaction was stirred under N₂ at rtovernight. The solvent was removed. The crude product was purified bynormal phase chromatography to give Intermediate 151C (92 mg, 53%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.85 (dd, J=2.6,0.7 Hz, 1H), 7.82 (dd, 1.8 Hz, 1H), 7.77 (dd, J=11.7, 1.8 Hz, 1H), 7.61(t, J=7.8 Hz, 1H), 3.92 (s, 3H). LC-MS(ESI) m/z: 238.0 [M+H]⁺.

Intermediate 151

To a solution of Intermediate 151C (92 mg, 0.39 mmol) in THF (2 mL) wereadded LiOH (27.9 mg, 1.16 mmol) and water (0.5 mL) at rt. The reactionwas stirred under N₂ at rt overnight. The reaction was acidified withTFA, and the solvent was removed. The crude product was purified byreverse phase chromatography to afford Intermediate 151 (42 mg, 49%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (br s, 1H), 8.27-8.19(m, 1H), 7.99 (s, 1H), 7.88-7.80 (m, 1H), 7.78-7.73 (m, 1H), 7.70 (dd,J=11.9, 1.5 Hz, 1H). LC-MS(ESI) m/z: 224.0 [M+H]⁺.

Intermediate 152: 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-fluorobenzoicacid

Intermediate 152A: methyl4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-fluorobenzoate

To a solution of Intermediate 151B, TFA salt (150 mg, 0.45 mmol) in DMF(5 mL) and H₂O (0.5 mL) were added sodium 2-chloro-2,2-difluoroacetate(137 mg, 0.90 mmol) and K₂CO₃ (155 mg, 1.12 mmol) at rt. The reactionwas stirred under N₂ at 110° C. for 5 h. After cooled to rt, Thereaction mixture was diluted with EtOAc, washed with H₂O and brine. Theorganic phase was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by normal phase chromatography to affordIntermediate 152A (76 mg, 63%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 8.26 (d, J=1.8 Hz, 1H), 8.06 (s, 1H), 7.85 (dd, J=8.0, 1.7 Hz, 1H),7.80 (dd, J=11.4, 1.5 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.24 (t, J=60.3Hz, 1H), 3.93 (s, 3H). LC-MS(ESI) m/z: 271.0 [M+H]⁺.

Intermediate 152

Intermediate 152 was prepared from Intermediate 152A following the samehydrolysis procedure as in Intermediate 149.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=1.5 Hz, 1H), 8.27 (s, 1H), 7.87(t, J=59.2 Hz, 1H), 7.71-7.66 (m, 2H), 7.62 (d, J=12.5 Hz, 1H).LC-MS(ESI) mm/z: 257.0 [M+H]⁺.

Intermediate 153:7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 153A: ethyl7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridine-3-carboxylate

To a suspension of Intermediate 150A (80 mg, 0.298 mmol) in THF (5 mL)was added methylmagnesium bromide (3 M in ether, 0.218 mL, 0.655 mmol)at −78° C. The reaction was stirred under N₂ at −78° C. for 1 h and thenwas warmed up to 0° C. After stirring for another 30 min, MeOH (0.5 mL)was added to quench the reaction. The solvent was removed. The crudeproduct was purified by normal phase chromatography to provideIntermediate 153A (16 mg, 22%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 9.17 (dd, J=7.3, 0.7 Hz, 1H), 8.22 (s, 1H), 7.89 (d, J=0.9 Hz, 1H),7.15 (dd, J=7.3, 1.8 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.62 (s, 6H), 1.40(t, J=7.2 Hz, 3H). LC-MS(ESI) m/z: 249.0 [M+H]⁺.

Intermediate 153

Intermediate 153 was obtained by following the same hydrolysis procedureas in Intermediate 149. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (d, J=7.3 Hz,1H), 7.64 (s, 1H), 7.46 (s, 1H), 6.98 (dd, J=7.3, 1.5 Hz, 1H), 5.16 (br.s., 1H), 1.45 (s, 6H). LC-MS(ESI) m/z: 221.0 [M+H]⁺;

Intermediate 154: 7-(1-hydroxyethyl)imidazo[1,2-a]pyridine-3-carboxylicacid

Intermediate 154A: ethyl7-(1-hydroxyethyl)imidazo[1,2-a]pyridine-3-carboxylate

To a solution of Intermediate 150A (80 mg, 0.30 mmol) in MeOH (3 mL) wasadded NaBH₄ (11.3 mg, 0.30 mmol) at 0° C. The reaction was stirred underN₂ at 0° C. for 2 h. It was quench with 1.0 N HCl, and the solvent wasremoved to leave the product as a white solid (70 mg, 100%). LC-MS(ESI)m/z: 235.0 [M+H]⁺.

Intermediate 154

Intermediate 154 was obtained by following the same hydrolysis procedureas in Intermediate 149. ¹H NMR (400 MHz, CD₃OD) δ 9.54 (d, J=7.3 Hz,1H), 8.55 (s, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.56 (dd, J=7.2, 1.4 Hz, 1H),5.05 (q, J=6.5 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H). LC-MS(ESI) m/z: 207.1[M+H]⁺.

Intermediate 155:7-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylicacid

Intermediate 155A: ethyl7-((1,1-dioxidotetrahydro-2H-thiopyran-4-yloxy)imidazo[1,2-a]pyridine-3-carboxylate

To a microwave vial containing ethyl7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (50 mg, 0.24 mmol),4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (73 mg, 0.49 mmol),1,1′-(azodicarbonyl)dipiperidine (184 mg, 0.73 mmol) were added toluene(3 mL) and tri-N-butylphosphine (0.18 mL, 0.73 mmol) at rt. The reactionwas heated with microwave at 150° C. for 15 min. The solvent wasremoved. The crude product was purified by normal phase chromatographyto provide Intermediate 155A (62 mg, 76%) as a white solid. LC-MS(ESI)m/z: 339.0 [M+H]⁺.

Intermediate 155

Intermediate 155 was obtained by following the same hydrolysis procedureas in Intermediate 149. ¹H NMR (400 MHz, CD₃OD) 9.43 (d, J=7.7 Hz, 1H),8.59 (s, 1H), 7.50 (d, J=2.2 Hz, 1H), 7.38 (dd, J=7.7, 2.4 Hz, 1H), 5.13(t, J=4.3 Hz, 1H), 3.47-3.37 (m, 2H), 3.30-3.21 (m, 2H), 2.54-2.43 (m,4H). LC-MS(ESI) m/z: 311.1 [M+H]⁺.

Intermediate 156:7-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 156 was obtained by following a similar procedure to thatdescribed in Intermediate 155. LC-MS(ESI) m/z: 275.1 [M+H]⁺.

Intermediate 157:7-((1,3-difluoropropan-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 157 was obtained by following a similar procedure to thatdescribed in Intermediate 155. LC-MS(ESI) mm/z: 257.1 [M+H]⁺.

Intermediate 158: 7-(pyridin-2-yloxy)imidazo[1,2-a]pyridine-3-carboxylicacid

Intermediate 158A: ethyl7-(pyridin-2-yloxy)imidazo[1,2-a]pyridine-3-carboxylate

To a solution of Intermediate 89 (30 mg, 0.15 mmol) in NMP (3 mL) wereadded 2-fluoropyridine (42 mg, 0.44 mmol) and K₂CO₃ (60 mg, 0.44 mmol)at it. The reaction was heated with microwave at 160° C. for 60 min. Thereaction was filtered. The crude product was purified by reverse phaseto provide Intermediate 158A (40 mg, 69%) as a light brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.25 (d, J=7.7 Hz, 1H), 8.40 (s, 1H), 8.30-8.22 (m,1H), 7.98 (ddd, J=8.2, 7.4, 2.0 Hz, 1H), 7.58 (d, J=2.2 Hz, 1H), 7.29(ddd, J=7.2, 4.9, 0.7 Hz, 1H), 7.26-7.20 (m, 2H), 4.38 (q, J=7.0 Hz,2H), 1.36 (t, J=7.0 Hz, 3H). LC-MS(ESI) m/z: 284.1 [M+H]⁺.

Intermediate 158

Intermediate 158 was obtained by following a similar hydrolysisprocedure to that described in Intermediate 155. ¹H NMR (400 MHz,methanol-d₄) δ 9.55 (dd, J=7.7, 0.7 Hz, 1H), 8.48 (s, 1H), 8.30 (ddd,J=4.9, 1.9, 0.7 Hz, 1H), 8.00 (ddd, J=8.1, 7.3, 2.0 Hz, 1H), 7.65 (dd,J=2.4, 0.7 Hz, 1H), 7.40 (dd, J=7.5, 2.4 Hz, 1H), 7.34 (ddd, 7.3, 5.0,0.9 Hz, 1H), 7.28-7.24 (m, 1H). LC-MS(ESI) m/z: 256.0 [M+H]⁺.

Intermediate 159: 3-isopropylimidazo[1,5-a]pyridine-1-carboxylic acid

Intermediate 159A: methyl3-(prop-1-en-2-yl)imidazo[1,5-a]pyridine-1-carboxylate

A microwave tube containing methyl3-bromoimidazo[1,5-a]pyridine-1-carboxylate (50 mg, 0.20 mmol),potassium trifluoro(prop-1-en-2-yl)borate (44 mg, 0.29 mmol), and K₃PO₄(125 mg, 0.59 mmol) was purged with nitrogen, and then were addeddioxane (3 mL), H₂O (0.5 mL) and XPhos-G2-Pd-preCat (15.4 mg, 0.020mmol). The reaction was heated with microwave at 150° C. for 15 min. Theorganic layer was separated, and the solvent was removed. The crudeproduct was purified by normal phase chromatography to affordIntermediate 159A (34 mg, 80%) as a white solid. LC-MS(ESI) m/z: 217.1[M+H]⁺.

Intermediate 159B: methyl3-isopropylimidazo[1,5-a]pyridine-1-carboxylate

To a solution of Intermediate 159A (34 mg, 0.157 mmol) in THF (3 mL) andMeOH (1 mL) were added TEA (0.11 mL, 0.79 mmol) and 10% Pd—C (16.7 mg,0.016 mmol) at rt. The reaction was stirred under a H₂ balloon at rt for1 h. The catalyst was filtered off, and the solvent was removed to givethe product (34 mg, 100%). LC-MS(ESI) m/z: 219.1 [M+H]⁺.

Intermediate 159

Intermediate 159 was obtained by following a similar hydrolysisprocedure to that described in Intermediate 155. LC-MS(ESI) m/z: 205.2[M+H]⁺.

Intermediate 160:7-(2,2-difluoroethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 160A: ethyl7-(2,2-difluoroethoxy)imidazo[1,2-a]pyridine-3-carboxylate

To a solution of Intermediate 89 (50 mg, 0.24 mmol) in THF (2 mL) wereadded 2-bromo-1,1-difluoroethane (70 mg, 0.49 mmol) and Cs₂CO₃ (158 mg,0.49 mmol) at rt. The reaction was heated at 50° C. for 24 h. Thesolvent was removed. The crude product was purified by normal phasechromatography to afford Intermediate 160A (42 mg, 64%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (d, J=7.5 Hz, 1H), 8.20 (s, 1H),6.99 (d, J=2.4 Hz, 1H), 6.78 (dd, J=7.5, 2.6 Hz, 1H), 6.15 (tt, J=54.8,4.4 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 4.27 (td, f=12.9, 4.0 Hz, 2H), 1.41(t, J=7.2 Hz, 3H). LC-MS(ESI) m/z; 271.0 [M+H]⁺.

Intermediate 160

Intermediate 160 was obtained by following a similar hydrolysisprocedure to that described in Intermediate 155. ¹H NMR (400 MHz,DMSO-d₆) δ 9.24-9.13 (m, 1H), 8.35 (s, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.13(dd, J=7.5, 2.6 Hz, 1H), 6.48 (tt, J=54.4, 3.3 Hz, 1H), 4.56 (td,J=14.7, 3.3 Hz, 2H). LC-MS(ESI) m/z: 243.0 [M+H]⁺.

Intermediate 161: 7-isopropoxyimidazo[1,2-a]pyridine-3-carboxylic acid

Intermediate 161 was obtained by following a similar procedure asdescribed in Intermediate 160. ¹H NMR (400 MHz, CD₃OD) δ 9.42 (dd,J=7.7, 0.4 Hz, 1H), 8.41 (s, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.20-7.14 (m,1H), 4.90 (spt, J=6.1 Hz, 1H), 1.45 (d, J=6.2 Hz, 6H). LC-MS(ESI) m/z:221.1 [M+H]⁺.

Example 1:N-[6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2,3-dihydro-1H-indene-2-carboxamide

Intermediate 1 (29 mg, 0.060 mmol) was dissolved in dry DMF (1 mL), then2,3-dihydro-1H-indene-2-carboxylic acid (19.5 mg, 0.120 mmol) and DIEA(0.063 mL, 0.360 mmol) were added. After stirring for 5 min at rt, HATU(22.8 mg, 0.060 mmol) was added, and the reaction mixture was stirred atrt for 2 h. The reaction mixture was quenched with MeOH (0.1 mL),diluted with DMF, filtered and was purified by preparative HPLC toafford Example 1 (15.3 mg, 63% yield). MS(ESI) m/z: 400.3 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.25 (d J=7.4 Hz, 1H), 8.17 (d,J=7.4 Hz, 1H), 7.96-7.89 (m, 1H), 7.88-7.75 (m, 2H), 7.17 (d J=4.4 Hz,2H), 7.14-7.05 (m, 2H), 4.14 (sxt, J=7.9 Hz, 1H), 3.93-3.82 (m, 1H),3.17-3.06 (m, 1H), 3.06-2.97 (m, 4H), 2.62-2.51 (m, 2H), 2.41-2.28 (m,3H), 2.24-2.13 (m, 1H), 2.06 (t, J=9.6 Hz, 1H), 1.88 (t, J=9.8 Hz, 1H).HPLC RT=1.52 min (Method E), 1.61 min (Method F).

The following Examples in Table 1 were made by using the same procedureas shown in Example 1. Intermediate 1 was coupled with the appropriateacid. Various coupling reagents could be used other than the onedescribed in Example 1 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 1 HPLC LCMS Meth- (M + od, RT Ex. R Name H)⁺ (min.) ¹H NMR  2

4-(dimethylamino)-N-[6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl]benzamide 403.2  E: 1.31 F: 1.40 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.21 (d, J= 7.4 Hz, 1H), 7.94-7.89 (m, 1H), 7.89-7.80 (m, 2H), 7.72 (d, J = 8.8Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.33 (sxt, J = 8.1 Hz, 1H), 3.95-3.81(m, 1H), 2.95 (s, 6H), 2.64-2.51 (m, 2H), 2.44-2.30 (m, 3H), 2.27-2.14(m, 2H), 2.04 (t, J = 9.9 Hz, 1H)  3

2-(naphthalen-1-yl)-N- [6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl]acetamide 424.3  E: 1.58 F: 1.67 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.43 (d, J = 7.4 Hz, 1H), 8.24 (d, J= 7.7 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.94-7.87 (m, 2H), 7.86-7.76(m, 3H), 7.56-7.47 (m, 2H), 7.47-7.42 (m, 1H), 7.42-7.37 (m, 1H), 4.09(sxt, J = 7.9 Hz, 1H), 3.88 (d, J = 12.1 Hz, 1H), 3.85 (s, 2H),2.60-2.52 (m, 1H), 2.40-2.27 (m, 3H), 2.22-2.11 (m, 1H), 2.11-2.02 (m,1H), 2.07 (t, J = 9.8 Hz, 1H), 1.93-1.82 (m, 1H)  4

2-(naphthalen-2-yl)-N- [6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl]acetamide 424.1  E: 1.68 F: 1.59 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.37 (d, J = 7.4 Hz, 1H), 8.24 (d, J= 7.7 Hz, 1H), 7.93-7.79 (m, 6H), 7.73 (s, 1H), 7.53-7.43 (m, 2H), 7.41(d, J = 8.1 Hz, 1H), 4.10 (sxt, J = 7.9 Hz, 1H), 3.92-3.79 (m, 1H), 3.53(s, 2H), 2.63- 2.52 (m, 1H), 2.40-2.26 (m, 3H), 2.22-2.12 (m, 1H), 2.05(t, J = 9.6 Hz, 1H), 1.87 (t, J = 9.8 Hz, 1H)  5

1-methyl-N-[6-(4-oxo- 3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan.-2-yl]-1H-indazole-3- carboxamide 414.2  E: 1.61 F: 1.51 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.52 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 7.7Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.95-7.89 (m, 1H), 7.90-7.80 (m, 2H),7.71 (d, J = 8.4 Hz, H), 7.45 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.4 Hz,1H), 4.48-4.33 (m, 1H), 4.12 (s, 3H), 3.89 (t, J = 8.4 Hz, 1H),2.64-2.53 (m, 2H), 2.46-2.28 (m, 4H), 2.24-2.07 (m, 2H)  6

N-[6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl]-3-phenylpropanamide 388.3  E: 1.42 F: 1.51 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.47 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 7.1 Hz, 1H),7.95-7.87 (m, 1H), 7.87-7.79 (m, 2H), 7.31-7.22 (m, 2H), 7.21-7.10 (m,3H), 4.15-4.02 (m, 1H), 3.85 (quin, J = 8.3 Hz, 1H), 2.78 (t, J = 7.6Hz, 2H), 2.57-2.52 (m, 1H), 2.37-2.25 (m, 5H), 2.18-2.09 (m, 1H), 1.97(t, J = 9.8 Hz, 1H), 1.80 (t, J = 9.9 Hz, 1H)  7

N-[6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-(2,2,2- trifluoroethyl)-1H- pyrazole-3-carboxamide 432.2  E: 1.47F: 1.47 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.29 (d, J = 7.6Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.97-7.76 (m, 4H), 6.73 (s, 1H), 5.18(q, J = 8.7 Hz, 2H), 4.40-4.23 (m, 1H), 3.88 (quin, J = 8.3 Hz, 1H),2.62-2.52 (m, 2H), 2.42-2.30 (m, 3H), 2.31-2.24 (m, 1H), 2.17 (d, J =5.8 Hz, 1H), 2.13-2.04 (m, 1H)  8

3-methyl-N-[6-(4-oxo- 3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H- pyrazole-4-carboxamide 440.25 E: 1.67 F: 1.67 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.84 (s, 1H), 8.25 (d, J = 7.6Hz, 1H), 8.11 (d, J = 6.7 Hz, 1H), 7.98- 7.80 (m, 3H), 7.74 (d, J = 7.6Hz, 2H), 7.52 ( J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 4.35-4.24 (m,1H), 3.90 (t, J = 8.2 Hz, 1H), 2.63 (br. s., 1H), 2.59-2.52 (m, 1H),2.41 (s, 3H), 2.37 (d, J = 8.2 Hz, 3H), 2.24 (br. s., 1H), 2.17 (t, J =9.8 Hz, 1H), 1.99 (t, J = 9.6 Hz, 1H)  9

1-tert-butyl-N-[6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl]-1H-pyrazole-4- carboxamide 406.2  E: 1.44 F:1.44 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.29- 8.20 (m, 2H),8.11 (d, J = 7.3 Hz, 1H), 7.95-7.88 (m, 1H), 7.86 (d, J = 9.5 Hz, 1H),7.83 (s, 2H), 4.34-4.22 (m, 1H), 3.95- 3.83 (m, 1H), 2.65-2.52 (m, 2H),2.43-2.32 (m, 3H), 2.20 (br. s., 1H), 2.14 (t, J = 9.6 Hz, 1H), 1.97 (t,J = 10.1. Hz, 1H), 1.51 (s, 9H) 10

N-[6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H- pyrazole-3-carboxamide 426.2  E: 1.71 F: 1.71 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.53 (s, 1H), 8.47 (d, J = 7.9Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.98- 7.80 (m, 5H), 7.53 (t, J = 7.6Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 6.87 (s, 1H), 4.42-4.32 (m, 1H), 3.90(quin, J = 8.4 Hz, 1H), 2.65-2.54 (m, 2H), 2.43-2.27 (m, 4H), 2.25-2.18(m, 1H), 2.17-2.09 (m, 1H) 11

1-(2-hydroxy-2- methylpropyl)-N-[6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl]-1H-indazole-3- 472.3  E: 1.59 F: 1.59 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.25(d, J = 7.9 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.96-7.81 (m, 3H), 7.76(d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H),4.48-4.39 (m, 1H), 4.37 (s, 2H), 3.90 (quin, J = 8.5 Hz, 1H), 2.67-2.53(m, 2H), 2.46-2.28 (m, 4H), 2.27-2.19 (m, 1H), 2.19-2.10 (m, 1H), 1.14(s, 6H) carboxamide 12

N-[6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H- pyrazole-4-carboxamide 436.2  E: 1.57 F: 1.57 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.87 (s, 1H), 8.35 (d, J = 7.3Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.96-7.78 (m, 4H), 7.52(t, J = 7.5 Hz, 2H), 7.40-7.32 (m, 1H), 4.38-4.27 (m, 1H), 3.90 (t, J =8.2 Hz, 1H), 2.63 (br. s., 1H), 2.59-2.52 (m, 2H), 2.44-2.31 (m, 3H),2.24 (br. s., 1H), 2.19 (t, J = 10.1 Hz, 1H), 2.02 (t, J = 9.9 Hz, 1H)13

5-methyl-N-[6-(4-oxo- 3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-phenyl-1H- pyrazole-4-carboxamide 440.2  E: 1.54 F: 1.55 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18(d, J = 7.0 Hz, 1H), 8.11 (s, 1H), 7.97- 7.80 (m, 3H), 7.54 (d, J = 7.0Hz, 2H), 7.49 (d, J = 6.7 Hz, 3H), 4.39-4.25 (m, 1H), 3.96-3.84 (m, 1H),3.36 (d, J = 5.2 Hz, 1H), 2.70-2.52 (m, 3H), 2.44-2.31 (m, 3H),2.27-2.14 (m, 2H), 2.03 (t, J = 10.1 Hz, 1H)

Example 14:1-Methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide

Intermediate 2 (13 mg, 0.035 mmol) was dissolved in dry DMF (1 mL), then1-methyl-1H-indazole-3-carboxylic acid (12.4 mg, 0.070 mmol) and DIEA(0.037 mL, 0.211 mmol) were added. After stirring for 5 min at rt, HATU(20 mg, 0.053 mmol) was added, and the reaction mixture was stirred atrt for 2 h. The reaction mixture was quenched with MeOH (0.1 mL),diluted with DMF, filtered and purified by preparative HPLC to affordExample 14 (11.2 mg, 75% yield). MS(ESI) m/z: 414.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.26 (d,J=7.7 Hz, 1H), 8, 16 (d, J=8.1 Hz, 1H), 7.98-7.81 (m, 3H), 7.72 (d,0.8.4 Hz, 1H), 7.46 (t J=7.6 Hz, 1H), 7.30-7.23 (m, 1H), 4.48-4.37 (m,1H), 4.13 (s, 3H), 3.95-3.85 (m, 1H), 2.65-2.55 (m, 2H), 2.46-2.29 (m,4H), 2.24-2.09 (m, 2H). HPLC RT=1.57 min (Method E), 1.52 min (MethodF).

Example 15:N-[(aR)-6-(4-Oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide

According to the procedure for the preparation of Example 14, couplingof Intermediate 2 (13 mg, 0.035 mmol) and1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (13.7 mg, 0.070mmol) afforded Example 15 (11.7 mg, 77% yield). MS(ESI) m/z: 432.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.32 (d, J=8.1Hz, 1H), 8.26 (d, J=7.7 Hz, 1H), 7.98-7.90 (m, 2H), 7.89-7.79 (m, 2H),6.75 (d, J=2.0 Hz, 1H), 5.20 (q, J=9.0 Hz, 2H), 4.33 (sxt, J=8.0 Hz,1H), 3.95-3.82 (m, 1H), 2.63-2.53 (m, 2H), 2.43-2.26 (m, 4H), 2.22-2.14(m, 1H), 2.14-2.04 (m, 1H). HPLC RT=1.34 min (Method E), 1.39 min(Method F).

Example 16:1-(2,2-Difluoroethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide

According to the procedure for the preparation of Example 14, couplingof Intermediate 2 (13 mg, 0.035 mmol) and1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylic acid (12.4 mg, 0.070mmol) afforded Example 16 (11.4 mg, 78% yield). MS(ESI) m/z; 414.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.27 (dd, J=14.8,8.1 Hz, 2H), 7.98-7.90 (m, 1H), 7.89-7.80 (m, 3H), 6.70 (s, 1H),6.56-6.25 (m, 1H), 4.75-4.64 (m, 2H), 4.39-4.27 (m, 1H), 3.89 (quin,J=8.2 Hz, 1H), 2.62-2.53 (m, 2H), 2.44-2.32 (m, 3H), 2.32-2.23 (m, 1H),2.22-2.14 (m, 1H), 2.13-2.03 (m, 1H). HPLC RT=1.23 min (Method E), 1.27min (Method F).

Example 17:1-Methyl-N-[(aS)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide

Intermediate 3 (13 mg, 0.035 mmol) was dissolved in dry DMF (1 mL), then1-methyl-1H-indazole-3-carboxylic acid (12.40 mg, 0.070 mmol) and DIEA(0.037 mL, 0.211 mmol) were added. After stirring for 5 min at rt, HATU(20.1 mg, 0.053 mmol) was added, and the reaction mixture was stirred atit for 2 h. The reaction mixture was quenched with MeOH (0.1 mL),diluted with DMF, filtered and purified by preparative HPLC to affordExample 17 (9.7 mg, 67% yield). MS(ESI) m/z: 414.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.26 (d,J=7.7 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.95-7.81 (m, 3H), 7.71 (d, J=8.4Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.30-7.23 (m, 1H), 4.48-4.37 (m, 1H),4.12 (s, 3H), 3.95-3.85 (m, 1H), 2.65-2.55 (m, 2H), 2.46-2.29 (m, 4H),2.22-2.09 (m, 2H). HPLC RT=1.57 min (Method E), 1.57 min (Method F).

Example 18:N-[(aS)-6-(4-Oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide

According to the procedure for the preparation of Example 17, couplingof Intermediate 3 (13 mg, 0.035 mmol) and1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (13.7 mg, 0.070mmol) afforded Example 18 (10.7 mg, 71% yield). MS(ESI) m/z: 432.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.32 (d, J=8.1Hz, 1H), 8.26 (d, J=7.7 Hz, 1H), 7.98-7.90 (m, 2H), 7.88-7.79 (m, 2H),6.73 (d, J=2.0 Hz, 1H), 5.21 (q, J=9.0 Hz, 2H), 4.33 (sxt, J=8.0 Hz,1H), 3.95-3.82 (m, 1H), 2.63-2.53 (m, 2H), 2.42-2.26 (m, 4H), 2.22-2.14(m, 1H), 2.14-2.01 (m, 1H). HPLC RT=1.39 min (Method E), 1.39 min(Method F).

Example 19:1-(2,2-Difluoroethyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-3-carboxamide

According to the procedure for the preparation of Example 17, couplingof Intermediate 3 (13 mg, 0.035 mmol) and1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylic acid (12.4 mg, 0.070mmol) afforded Example 19 (9.9 mg, 67%/o yield). MS(ESI) m/z; 414.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.27 (dd, J=14.8,8.1 Hz, 2H), 7.99-7.90 (m, 1H), 7.89-7.80 (m, 3H), 6.70 (s, 1H),6.56-6.25 (m, 1H), 4.78-4.64 (m, 2H), 4.39-4.27 (m, 1H), 3.89 (quin,J=8.2 Hz, 1H), 2.62-2.53 (m, 2H), 2.44-2.32 (m, 3H), 2.32-2.23 (m, 1H),2.25-2.14 (m, 1H), 2.13-2.03 (m, 1H). HPLC RT=1.27 min (Method E), 1.27min (Method F).

The following Examples in Table 2 were made by using the same procedureas shown in Example 14. Intermediate 2 was coupled with the appropriateacid. Various coupling reagents could be used other than the onedescribed in Example 14 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 2 HPLC LCMS Meth- (M + od, RT Ex. R Name H)⁺ (min.) ¹H NMR 20

5-methyl-N-[(aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1- phenyl-1H-pyrazole-4- carboxamide 440.4 E:1.56 F: 1.56 ¹H MR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J =7.9 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.11 (s, 1H), 7.97- 7.89 (m, 1H),7.89-7.77 (m, 2H), 7.60-7.41 (m, 5H), 4.38- 4.25 (m, 1H), 3.95-3.84 (m,1H), 2.66-2.53 (m, 2H), 2.48 (s, 3H), 2.43-2.30 (m, 3H), 2.26-2.13 (m,2H), 2.07-1.96 (m, 1H) 21

1-(2-hydroxy-2-methylpropyl)- N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- indazole-3-carboxamide 472.5 E: 1.57 F:1.57 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.42 (d, J = 7.9Hz, 1H), 8.25 (d, J = 7.9 Hz. 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.96-7.80(m, 3H), 7.76 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.22 (t, J= 7.5 Hz, 1H), 4.76 (s, 1H), 4.47-4.39 (m, 1H), 2.66-2.55 (m, 2H), 2.54(s, 2H), 2.45-2.30 (m, 4H), 2.26- 2.12 (m, 2H, 1.14 (s, 6H) 22

N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1-(3,3,3-trifluoropropyl)-1H- pyrazole-3-carboxamide 446.3 E: 1.53 F: 1.53¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.32- 8.16 (m, 2H),7.99-7.71 (m, 5H), 6.61 (s, 1H), 4.42 (t, J = 6.9 Hz, 2H), 4.34-4.20 (m,1H), 3.93-3.78 (m, 2H), 3.05-2.89 (m, 3H), 2.42-2.30 (m, 4H), 2.11-1.98(m, 1H) 23

1-(cyclopropyl)-N-[(aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-3-carboxamide 404.4 E: 1.51 F: 1.51 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),8.19 (d, J = 8.2 Hz, 1H), 7.95-7.77 (m, 4H), 6.61 (d, J = 2.1 Hz, 1H),4.31 (sxt, J = 8.2 Hz, 1H), 4.00 (d, J = 7.3 Hz, 2H), 3.92-3.79 (m, 1H),2.61-2.52 (m, 2H), 2.41- 2.30 (m, 3H), 2.27 (t, J = 9.9 Hz, 1H),2.21-2.14 (m, 1H), 2.11- 2.02 (m, 1H), 1.3H.20 (m, 1H), 0.57-0.48 (m,2H), 0.37 (q, J = 4.9 Hz, 2H) 24

3-cyclopropyl-1-methyl-N- [(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-5-carboxamide 404.6 E: 1.51 F:1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H) 8.46 (d, J = 7.6 Hz,1H), 8.24 (d, J = 7.6 Hz, 1H), 7.95-7.89 (m, 1H) 7.89-7.77 (m, 2H), 6.51(s, 1H), 4.33-4.18 (m, 1H), 3.91 (s, 3H), 3.87 (d, J = 8.5 Hz, 1H),2.64-2.52 (m, 2H), 2.42-2.29 (m, 3H), 2.24-2.13 (m, 2H), 2.01 (t, J =9.9 Hz, 1H), 1.88- 1.77 (m, 1H), 0.86 (d, J = 7.3 Hz, 2H), 0.59 (d, J =4.9 Hz, 2H) 25

1-methyl-N-[(aR)-6-4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-3- (trifluoromethyl)- 1H-pyrazole-5-carboxamide 432.2 E: 1.72 F: 1.72 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48(s, 1H), 8.80 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.96-7.89(m, 1H), 7.88-7.76 (m, 2H), 7.31 (s, 1H), 4.36-4.22 (m, 1H), 4.10 (s,3H), 3.89 (quin, J = 8.5 Hz, 1H), 2.68-2.58 (m, 1H), 2.43- 2.30 (m, 3H),2.28-2.15 (m, 2H), 2.09-1.96 (m, 1H) 26

5-cyclopropyl-1-methyl-N- [(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-3-carboxamide 404.2 E: 1.51 F:1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.46 (d, J = 7.6Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.95-7.88 (m, 1H 7.87-7.78 (m, 2H),6.52 (s, 1H), 4.32-4.20 (m, 1H), 3.91 (s, 3H), 3.89-3.81 (m, 1H),2.66-2.53 (m, 2H), 2.42-2.28 (m, 3H), 2.21-2.12 (m, 2H), 2.01 (t, J =9.9 Hz, 1H), 1.86-1.76 (m, 1H), 0.91-0.80 (m, 2H), 0.59 (d, J = 3.1 Hz,2H) 27

1-cyclopropyl-N-[(aR)- 6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-4-carboxamide 390.2 E: 1.22 F:1.14 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.24 (d, J = 7.7Hz, 1H), 8.20-8.1:3 (m, 2H), 7.95-7.88 (m, 1H), 7.88- 7.76 (m, 3H),4.31-4.20 (m, 1H), 3.87 (quin, J = 8.4 Hz, 1H), 3.76-3.68 (m, 1H),2.62-2.55 (m, 1H), 2.41-2.27 (m, 3H.), 2.23-2.08 (m, 2H), 1.96 (t, J =9.9 Hz, 1H), 1.05-0.98 (m, 2H), 0.99-0.92 (m, 7H) 28

5-(difluoromethoxy)-1-methyl- N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-3-carboxamide 430.1 E: 1.46 F:1.47 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.37 (d, J = 8.1.Hz, 1H), 8.26 (d, J = 8.1. Hz, 1H), 7.99-7.81 (m, 4H), 7.24 (t., J =72.7 Hz, 1H), 6.38 (s, 1H), 4.31 (sxt, J = 8.1 Hz, 1H), 3.94-3.84 (m,1H), 3.73 (s, 3H), 2.43-2.31 (m, 3H), 2.31- 2.22 (m, 1H), 2.21-2.14 (m,1H), 2.12-2.03 (m, 1H) 29

1-cyclopropyl-N-[(aR)-6- (4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-3-carboxamide 390.2 E: 1.4 F:1.41 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.98-7.79 (m, 5H), 6.57 (d, J = 2.0Hz, 1H), 4.31 (sxt, J = 8.1 Hz, 1H), 3.93-3.82 (m, 1H), 3.77 (tt, J =7.3, 3.7 Hz, 1H), 2.42-2.30 (m, 3H), 2.30- 2.23 (m, 1H), 2.20-2.0:3 (m,2H), 1.13-1.06 (m, 2H), 1.03- 0.93 (m, 2H) 30

1-(2-hydroxy-2-methylpropyl)- N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1H- pyrazole-3-carboxamide 422.2 E: 1.22 F:1.22 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.97-7.88 (m, 2H), 7.88-7.79 (m, 2H),7.71 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 4.32 (sxt, J = 8.1Hz, 1H), 4.05 (s, 2H), 3.88 (quin, J = 8.5 Hz, 1H), 2.62-2.55 (m, 1H),2.42-2.31 (m, 3H), 2.26 (t, J = 9.8 Hz, 1H), 2.21-2.13 (m, 1H),2.12-2.04 (m, 1H), 1.06 (s, 6H) 31

6-fluoro-1-(2-hydroxy-2- methylpropyl)-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1H-indazole-3-carboxamide 490.2 E: 1.56 F: 1.54 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.45 (s, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.21 (d., J = 7.7 Hz,1H), 8.08 (dd, J = 8.9, 5.6 Hz, 1H), 7.91-7.75 (m, 3H), 7.58 (d, J = 8.8Hz, 1H), 7.08 (t, J = 8.2 Hz, 1H), 4.37 (sxt, J = 8.2 Hz, 1H), 4.30 (s,2H), 3.86 (quin, J = 8.5 Hz, 1H), 2.61-2.52 (m, 2H), 2.40-2.25 (m, 4H),2.22-2.07 (m, 2H), 1.10 (s, 6H) 32

1-(2,2-difluoroethyl)-3-methyl- N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1H-pyrazole-4-carboxamide 428.2 E: 1.20 F: 1.18 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.16 (s, 1H), 8.09 (d, J= 7.4 Hz, 1H), 7.97- 7.81 (m, 3H), 6.34 ((t, J = 54.5, 3.4 Hz, 1H), 4.56(td, J = 15.4, 3.2 Hz, 2H), 4.31-4.21 (m, 1H), 3.88 (quin, J = 8.5 Hz,1H), 2.63-2.56 (m, 1H), 2.41-2.32 (m, 3H), 2.30 (s, 3H), 2.23- 2.10 (m,2H), 1.97 (t, J = 10.1 Hz, 1H)

Example 33:4-Methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-2-(piperidin-1-yl)thiazole-5-carboxamide

Intermediate 22 (10 mg, 0.022 mmol), piperidine (0.016 mL, 0.16 mmol)and DIEA (0.038 mL, 0.22 mmol) were dissolved in anhydrous NMP (1.5 mL).Then the reaction vial was capped, and the mixture was stirred at 150°C., for 15 min under microwave irradiation. The reaction mixture wascooled to rt, quenched with TFA (few drops), filtered, and purified bypreparative HPLC to afford Example 33 (7.6 mg, 69% yield). MS(ESI) m/z:464.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.62 (s, 1H), 8.39 (d,J=7.7 Hz, 1H), 8.11-7.94 (m, 3H), 7.88 (d, J=7.4 Hz, 1H), 4.37 (sxt,J=8.0 Hz, 1H), 4.02 (quin, J=8.5 Hz, 1H), 2.76-2.59 (m, 5H), 2.50-2.42(m, 3H), 2.37-2.26 (m, 2H), 2.15 (t J=9.9 Hz, 1H), 1.72 (br. s., 6H).HPLC RT=1.21 min (Method E), 1.40 min (Method F).

The following Examples in Table 3 were made by using the same procedureas shown in Example 33. Intermediate 22 was coupled with the amine.Various solvents could be used other than the one described in Example33 such as TEA, DBU, DABCO. Various solvents could be used other thanthe one described in Example 33 such as DMF, n-butanol, DMPU, THF.

TABLE 3 HPLC LCMS Meth- (M + od, RT Ex. R Name H)⁺ (min.) ¹H NMR 34

4-methyl-2-(molphohn-4-yl)-N- [(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3- thiazole-5-carboxamide 466.1 E: 1.14 F:1.34 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.24 (d, J = 7.7Hz, 1H), 7.98-7.75 (m, 4H), 4.23 (sxt, J = 8.1 Hz, 1H), 3.87 (quin, J =8.5 Hz, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.43-3.31 (m, 1H), 2.60-2.51 (m,2H), 2.42- 2.30 (m, 6H), 2.25-2.12 (m, 2H), 2.01 (t, J = 9.9 Hz, 1H) 35

4-methyl-N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-2- (pyrrolidin-1-yl)-1,3-thiazole-5-carboxamide 450.2 E: 1.39 F: 1.53 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.59(s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.08-7.92 (m, 3H), 7.85 (d, J = 7.4Hz, 1H), 4.40-4.29 (m, 1H), 4.05-3.93 (m., 1H), 2.68- 2.58 (m, 6H),2.49-2.41 (m, 3H), 2.37-2.23 (m, 2H), 2.18-2.00 (m, 5H) 36

2-[(3S)-3-fluoropyrrolidin-1- yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 468.3 E: 1.20 F: 1.43 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.48 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.95-7.88 (m, 1H),7.87-7.75 (m, 3H), 5.43 (d, J = 52.8 Hz, 1H), 4.29-4.15 (m, 1H), 3.87(quin, J = 8.4 Hz, 1H), 2.57-2.52 (m, 4H), 2.38 (s, 3H), 2.36-2.26 (m,4H), 2.25-2.09 (m, 3H), 2.01 (t, J = 9.9 Hz, 1H) 37

2-[(3R)-3-fluoropyrrolidin-1- yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 468.3 E: 1.20 F: 1.43 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.44 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.91-7.85 (m, 1H),7.84-7.71 (m, 3H), 5.39 (d, J = 53.9 Hz, 1H), 4.24-4.12 (m, 1H) 3.83(quin, J = 8.5 Hz, 1H), 3.43-3.32 (m, 1H), 2.46 (br. s., 6H), 2.34 (s,3H), 2.31-2.19 (m, 4H), 2.18-2.07 (m, 2H), 2.01-1.91 (m, 1H) 38

2-[(3S)-3-cyanopyrrohdin-1- yl]-4-tnethyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 475.2 E: 1.19 F: 1.36 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.44 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.90-7.84 (m, 1H), 7.80(dd, J = 12.1, 6.4 Hz, 3H), 4.24-4.12 (m, 1H), 3.83 (quin, J = 8.5 Hz,1H), 3.72-3.64 (m, 1H), 3.45-3.30 (m, 1H), 2.46 (br. s., 4H), 2.40-2.35(m, 1H), 2.34 (s, 3H), 2.33-2.19 (m, 4H), 2.17-2.06 (m, 2H), 2.01-1.91(m, 1H) 39

2-[(3R)-3-cyanopyrrolidin-1- yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 475.2 E: 1.18 F: 1.36 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.44 (s, 1H), 8.20 (d,.1-7.7 Hz, 1H), 7.91-7.84 (m, 1H),7.84-7.72 (m, 3H), 4.17 (sxt, J = 8.0 Hz, 1H), 3.83 (quin, J = 8.4 Hz,1H), 3.72-3.63 (m, 1H), 3.48-3.31 (m, 2H), 2.46 (br. s., 4H), 2.41-2.35(m, 1H), 2.33 (s, 3H), 2.32-2.20 (m, 4H), 2.17-2.06 (m, 2H), 1.96 (t, J= 9.9 Hz, 1H) 40

rel-2-[(1S,5R)-2- azabicyclo[3.1.0]hexan-2-yl]-4-methyl-N-[(aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl]-1,3- thiazole-5-carboxamide 462.3 E: 1.24 F:1.54 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.44 (s, 1H), 8.20 (d, J = 7.7Hz, 1H), 7.91-7.84 (m, 1H), 7.83-7.72 (m, 3H), 4.22-4.12 (m, 1H), 3.82(quin, J = 8.4 Hz, 1H), 3.29 (br. s., 1H), 3.04-2.92 (m, 1H), 2.46 (br.s., 4H), 2.32 (s, 3H), 2.31-223 (m, 2H), 2.21-2.05 (m, 3H), 1.97 (q, J =10.2 Hz, 2H), 1.71-1.62 (m, 1H), 0.80-0.71 (m, 1H), 0.54 (br. s., 1H) 41

2-(3,3-difluoropyrrolidin-1-yl)- 4-methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 486.2 E: 1.38 F: 1.55 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.48 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.96-7.77 (m, 4H),4.29-4.13 (m, 1H), 3.93-3.76 (m, 3H), 2.69-2.53 (m, 4H), 2.38 (s, 3H),2.36-2.27 (m, 3H), 2.23-2.10 (m, 2H), 2.01 (t, J = 10.1 Hz, 1H) 42

2-(cyclopropylamino)-4- methyl-N-[(aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl]-1,3-thiazole-5-carboxamide 436.2 E: 1.07 F: 1.30 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.47 (s, 1H), 8.29 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.98-7.80(m, 4H), 7.73 (d, J = 7.7 Hz, 1H), 4.29-4.18 (m, 1H), 3.95-3.81 (m, 1H),2.35 (m, 6H), 2.24-1.96 (m, 4H), 0.72 (d, J = 5.0 Hz, 2H), 0.52 (br. s.,2H)

Example 43:4-((aR)-6-((5-Phenyl-1,3,4-thiadiazol-2-yl)amino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one(2H)-one

Intermediate 2, HCl (16 mg, 0.055 mmol) and DIEA (0.096 mL, 0.55 mmol)were dissolved in NMP (1.5 mL), and 2-chloro-5-phenyl-1,3,4-thiadiazole(27.0 mg, 0.137 mmol) was added. The reaction mixture was stirred at150° C., for 6 h. The reaction mixture was cooled to rt, diluted withDMF, filtered, and purified by preparative HPLC to afford Example 43(11.4 mg, 0.027 mmol, 50% yield). MS(ESI) m/z: 416.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.24 (dd J=12.8, 7.3 Hz, 2H),7.96-7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.74 (d, J=7.0 Hz, 2H), 7.51-7.37(m, 3H), 4.11-3.99 (m, 1H), 3.90 (quin, J=8.4 Hz, 1H), 2.78-2.68 (m,1H), 2.61-2.53 (m, 1H), 2.44-2.29 (m, 4H), 2.17-2.09 (m, 1H), 1.94 (ddJ=11.1, 8.4 Hz, 1H). HPLC RT=1.51 min (Method E), 1.68 min (Method F).

Example 44:4-((aR)-6-((5-phenyloxazol-2-yl)amino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one(2H)-one

According to the procedure for the preparation of Example 43, couplingof Intermediate 2. HCl (16 mg, 0.055 mmol) and 2-chloro-5-phenyloxazole(24.6 mg, 0.137 mmol) afforded Example 44 (6.4 mg, 0.016 mmol, 29%yield). MS(ESI) m/z: 399.4 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.43(s, 1H), 10.15 (br. s., 1H), 8.23 (d, J=7.6 Hz, 1H), 7.92-7.86 (m, 1H),7.84-7.78 (m, 2H), 7.46-7.40 (m, 2H), 7.38-7.32 (m, 1H), 7.30 (d, J=7.0Hz, 2H), 6.41 (d, J=2.1 Hz, 1H), 4.24 (quin, J=8.7 Hz, 1H), 3.84 (quin,J=8.3 Hz, 1H), 2.99 (t, J=9.9 Hz, 1H), 2.84 (t, J=10.2 Hz, 1H), 2.45 (d,J=8.2 Hz, 3H), 2.36-2.23 (m, 2H), 2.10-2.01 (m, 1H). HPLC RT=1.55 min(Method E), 1.54 min (Method F).

Example 45:4-((aR)-6-(Phthalazin-1-ylamino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one(2H)-one

According to the procedure for the preparation of Example 43, couplingof Intermediate 2. HCl (16 mg, 0.055 mmol) and 1-chlorophthalazine(22.56 mg, 0.137 mmol) afforded Example 45 (2.4 mg, 11% yield). MS(ESI)m/z: 384.4 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.00(s, 1H), 8.71 (d, J=7.6 Hz, 1H), 8.26 (d, =7.6 Hz, 1H), 8.20-8.08 (m,3H), 7.98-7.91 (m, 1H), 7.89-7.79 (m, 2H), 4.50-4.39 (m, 1H), 4.00-3.90(m, 1H), 2.92-2.82 (m, 1H), 2.61 (t, J=7.6 Hz, 1H), 2.48-2.34 (m, 4H),2.31-2.20 (m, 1H). HPLC RT=1.14 min (Method E), 1.40 min (Method F).

Example 46:4-(6-(Indoline-1-carbonyl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one(2H)-one

Intermediate 4 (20 mg, 0.070 mmol) was dissolved in dry DMF (1 mL), thenindoline (0.014 mL, 0.13 mmol) and DIEA (0.067 mL, 0.38 mmol) wereadded. After stirring for 5 min at rt, HATU (24.3 mg, 0.064 mmol) wasadded, and the reaction mixture was stirred at 60° C., for 2 h. Thereaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,filtered and purified by HPLC to afford Example 46 (20.0 mg, 0.049 mmol,77% yield). MS(ESI) m/z: 386.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.46 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.95-7.88(m, 1H), 7.88-7.77 (m, 2H), 7.21 (d, J=7.3 Hz, 1H), 7.13 (t, J=7.5 Hz,1H), 6.97 (t, J=7.2 Hz, 1H), 4.04-3.94 (m, 2H), 3.86 (quin, J=8.4 Hz,1H), 3.11 (t, J=8.4 Hz, 2H), 2.57 (d, J=7.3 Hz, 1H), 2.48-2.33 (m, 4H),2.32-2.17 (m, 2H), 2.15 (d, J=8.5 Hz, 1H). HPLC RT=1.78 min (Method E),1.78 min (Method F).

The following Examples in Table 4 were made by using the same procedureas shown in Example 46. Intermediate 4 was coupled with the appropriateamine. Various coupling reagents could be used other than the onedescribed in Example 46 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 4 LCMS HPLC (M + Method, Ex. R Name H)⁺ RT (min.) ¹H NMR 47

4-[6-(2,3-dihydro-1H-isoindole- 2-carbonyl)spiro[3.3]heptan-2-yl]-1,2-dihydrophthalazin-1-one 386.2 E: 1.64 F: 1.64 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.46 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95-7.89 (m,1H), 7.87-7.79 (m, 2H), 7.39-7.25 (m, 4H), 4.74 (br. s., 2H), 4.62 (s,2H), 3.86 (quin, J = 8.3 Hz, 1H), 3.28 (quin, J = 8.4 Hz, 1H), 2.62-2.55(m, 1H), 2.43-2.32 (m, 3H), 2.30-2.23 (m, 1H), 2.21-2.10 (m, 2H) 48

N-(5-methyl-1,3,4-thiadiazol-2- yl)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptane-2- carboxamide 382.4 E: 1.31 F: 1.31 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.94-7.89(m, 1H), 7.87-7.79 (m, 2H), 3.85 (quin, J = 8.5 Hz, 1H), 3.28 (quin, J =8.4 Hz, 1H), 2.59 (s, 3H), 2.49-2.44 (m, 2H), 2.43-2.32 (m, 3H),2.31-2.23 (m, 1H), 2.21-2.08 (m, 2H) 49

N-(5-methyl-1,2-oxazol-3-yl)-6- (4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptane-2- carboxamide 365.2 E: 1.38 F: 1.38 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.45 (s, 1H), 10.69 (s, 1H), 8.24 (d, J = 7.9 Hz,1H), 7.95-7.88 (m, 1H), 7.87- 7.79 (m, 2H), 6.62 (s, 1H), 3.85 (quin, J= 8.4 Hz, 1H), 3.16 (t, J = 8.2 Hz, 1H), 2.58-2.52 (m, 1H), 2.43-2.32(m, 7H), 2.30- 2.23 (m, 1H), 2.18-2.11 (m, 1H), 2.10-2.01 (m, 1H)

Example 50:N-((aR)-6-(4-Oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide

Example 50A: 4-Nitrophenyl((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Intermediate 2, HCl was suspended in anhydrous THF (3 mL), and DIEA(0.049 mL, 0.28 mmol) was added. The reaction mixture was cooled to 0°C., and 4-nitrophenyl carbonochloridate (27.4 mg, 0.136 mmol) was addedin one portion. The reaction mixture was stirred at 0° C., for 30 min.The reaction mixture was filtered through a membrane filter, and Example50A was used as is in the subsequent urea formation step. MS(ESI) m/z:421.0 (M+H)⁺.

Example 50

Indoline (0.016 mL, 0.14 mmol) and DIEA (0.029 mL, 0.17 mmol) wasdissolved in anhydrous THF (0.5 mL), and Example 50A (0.056 mmol) wasadded. The reaction mixture was stirred at rt for 5 min and then at 50°C., for 15 min. The reaction mixture was concentrated, diluted with DMF,filtered and purified by preparative HPLC to afford Example 50 (13.1 mg,58% yield). MS(ESI) m/z: 401.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.46 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.96-7.89 (m, 1H), 7.88-7.75 (m,3H), 7.12 (d, J=7.3 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.81 (t F J=7.3 Hz,1H), 6.67 (d, J=1=7.3 Hz, 1H), 4.13 (sxt, J=8.1 Hz, 1H), 3.90-3.82 (m,2H), 3.08 (t, J=8.7 Hz, 2H), 2.62-2.54 (m, 2H), 2.43-2.30 (m, 3H),2.22-2.12 (m, 2H), 2.02 (t J=10.1 Hz, 1H). HPLC RT=1.64 min (Method E),1.64 min (Method F).

Example 51:N-((aR)-6-(4-Oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)isoindoline-2-carboxamide

According to the procedure for the preparation of Example 50, reactionof Example 50A (0.056 mmol) and isoindoline (0.016 mL, 0.140 mmol)afforded Example 51 (16.4 mg, 73% yield). MS(ESI) m/z: 401.2 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) ppm 12.41 (s, 1H), 8.21 (d, J=7.6 Hz, 1H),7.90-7.76 (m, 3H), 7.30-7.20 (m, 4H), 6.40 (d, J=7.6 Hz, 1H), 4.53 (s,4H), 4.11-4.00 (m, 1H), 3.84 (quin, J=8.5 Hz, 1H), 2.53 (br. s., 1H),2.37-2.25 (m, 3H), 2.16-2.06 (m, 2H), 1.94 (t, J=9.9 Hz, 1H). HPLCRT=1.53 min (Method E), 1.53 min (Method F).

Example 52:4-(6-(2-(Indolin-1-yl)-2-oxoethyl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

Intermediate 5 (5.1 mg, 0.017 mmol) was dissolved in dry DMF (1 mL),then indoline (3.5 μl, 0.031 mmol) and DIEA (0.016 mL, 0.093 mmol) wereadded. After stirring for 5 min at rt, HATU (5.9 mg, 0.016 mmol) wasadded, and the reaction mixture was stirred at it for 2 h. The reactionmixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered andpurified by preparative HPLC to afford Example 52 (2.0 mg, 32% yield).MS(ESI) m/z: 400.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.45 (s,1H), 8.24 (d, J=7.9 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.94-7.88 (m, 1H),7.86-7.78 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.96(t, J=7.3 Hz, 1H), 4.04 (t, J=8.4 Hz, 2H), 3.83 (quin, J=8.4 Hz, 1H),3.59 (br. s., 2H), 3.11 (t, J=8.4 Hz, 2H), 2.42 (br. s., 1H), 2.34 (d,J=9.2 Hz, 3H), 2.29-2.21 (m, 1H), 2.12-2.01 (m, 1H), 1.87 (d, J=7.3 Hz,1H), 1.70-1.60 (m, 1H). HPLC RT=1.88 min (Method E), 1.88 min (MethodF).

Example 53:2-((R)-3-fluoropyrrolidin-1-yl)-5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)thiazole-4-carboxamide

Intermediate 2, HCl and Intermediate 23 were coupled in a mannerdescribed in Example 14 to afford Example 53 (36.8 mg, 86% yield).MS(ESI) m/z: 468.2. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25(d, J=−7.7 Hz, 1H), 7.97 (br d, J=8.1 Hz, 1H), 7.94-7.88 (m, 1H),7.88-7.79 (m, 2H), 5.38 (d, J=52.8 Hz, 1H), 4.32-4.20 (m, 1H), 3.88(quin, J=8.4 Hz, 1H), 3.77-3.63 (m, 1H), 2.61-2.55 (m, 1H), 2.54 (s,3H), 2.42-2.32 (m, 3H), 2.30-2.12 (m, 4H), 2.09-2.01 (m, 1H). HPLC RT=E:1.56 F: 1.73.

The following Examples in Table 5 were prepared by using a similarprocedure as shown in Example 33. Intermediate 24 was coupled with theamine. Various bases could be used other than the one described inExample 33 such as TEA, DBU, DABCO. Various solvents could be used otherthan the one described in Example 33 such as DMF, n-butanol, DMPU, THF.

TABLE 5 LCMS HPLC (M + Method, Ex. R Name H)⁺ RT (min.) ¹H NMR 54

2-(3,3-difluoropyrrolidin-1-yl)- 5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)thiazole-4-carboxamide486.2 E: 1.80 F: 1.84 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.24 (d, J = 7.7 Hz, 1H), 8.03 (br d, J = 8.4 Hz, 1H), 7.95-7.88 (m,1H), 7.88-7.79 (m, 2H), 4.31-4.20 (m, 1H), 3.87 (br t, J = 12.6 Hz, 3H),2.62-2.55 (m, 2H), 2.54 (s, 3H), 2.40-2.28 (m, 3H), 2.25-2.12 (m, 2H),2.08-2.00 (m, 1H) 55

2-((5)-3-cyanopyrrolidin-1-yl)- 5-methyl-N-((aR)-6-(4-oxo-3,4-dihydmphthalazin-1- yl)spiro[3.3]heptan-2- yl)thiazole-4-carboxamide475.3 E: 1.52 F: 1.59 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.24 (d, J = 7.7 Hz, 1H), 7.99 (br d, J = 8.1 Hz, 1H), 7.94-7.89 (m,1H), 7.88-7.79 (m, 2H), 4.33-4.20 (m, 1H), 3.88 (quin, J = 8.4 Hz, 1H),3.78-3.70 (m, 1H), 3.70-3.62 (m, 1H), 2.56 (br s, 2H), 2.54 (s, 3H),2.44-2.32 (m, 4H), 2.31-2.12 (m, 3H), 2.09-1.98 (m, 1H) 56

2-((R)-3-cyanopyrrolidin-1-yl)- 5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)thiazole-4-carboxamide475.2 E: 1.53 F: 1.59 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.25 (d, J = 7.7 Hz, 1H), 7.99 (br d, J = 8.1 Hz, 1H), 7.95-7.89 (m,1H), 7.89-7.80 (m, 2H), 4.33-4.20 (m, 1H), 3.89 (quin, J = 8.4 Hz, 1H),3.79-3.72 (m, 1H), 3.71-3.62 (m, 1H), 3.62-3.53 (m, 1H), 2.61- 2.55 (m,2H), 2.54 (s, 3H), 2.44-2.32 (m, 4H), 2.31- 2.13 (m, 3H), 2.10-2.01 (m,1H) 57

2-((3,3-difluorocyclobutyl) amino)-5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)thiazole-4-carboxamide 486.3 E: 1.68 F: 1.72 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.90 (br d, J =7.1 Hz, 1H), 7.88-7.79 (m, 3H), 4.29-4.19 (m, 1H), 4.09 (br s, 1H),3.92-3.81 (m, 1H), 3.09-2.96 (m, 2H), 2.64- 2.56 (m, 2H), 2.54 (s, 3H),2.41-2.27 (m, 3H), 2.24- 2.12 (m, 2H), 2.03 (br t, J = 9.9 Hz, 1H) 58

2-((S)-3-fluoropyrrolidin-1-yl)- 5-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)thiazole-4-carboxamide468.2 E: 1.55 F: 1.72 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H),8.25 (br d, J = 7.7 Hz, 1H), 7.96 (br d, J = 8.4 Hz, 1H), 7.94-7.88 (m,1H), 7.88-7.80 (m, 2H), 5.53-5.34 (m, 1H), 4.32-4.21 (m, 1H), 3.95-3.83(m, 1H), 3.78-3.63 (m, 1H), 2.63 (br s, 2H), 2.57-2.54 (m, 3H),2.43-2.33 (m, 3H), 2.31-2.13 (m, 4H), 2.10- 2.01 (m, 1H) 59

5-methyl-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-2-((S)- 2-(trifluoromethyl) pyrrolidin-1-yl)thiazole-4-carboxamide 518.2 E: 2.01 F: 2.02 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.24 (br d, J = 8.1 Hz, 1H), 7.96 (br d, J= 8.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.87-7.80 (m, 2H), 4.75 (br t, J = 7.7Hz, 1H), 4.30-4.21 (m, 1H), 3.88 (br t, J = 8.2 Hz, 1H), 2.98 (s, 3H),2.41-2.31 (m, 3H), 2.19 (br d, J = 8.4 Hz, 3H), 2.11-1.96 (m, 4H) 60

5-methyl-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-2-((R)- 2-(trifluoromethyl) pyrrolidin-1-yl)thiazole-4-carboxamide 518.2 E: 2.00 F: 2.02 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.96 (br d, J =8.1 Hz, 1H), 7.94-7.88 (m, 1H), 7.88-7.79 (m, 2H), 4.77 (br t, J = 7.6Hz, 1H), 4.31-4.21 (m, 1H), 3.94-3.83 (m, 1H), 3.57 (br s, 1H), 2.56 (s,3H), 2.42-2.32 (m, 3H), 2.19 (br d, J = 6.7 Hz, 3H), 2.12-1.97 (m, 4H)

The following Examples in Table 6 were made by using the same procedureas shown in Example 14. Intermediate 2 was coupled with the appropriateacid. Various coupling reagents could be used other than the onedescribed in Example 14 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 6 HPLC LCMS Meth- (M + od, RT Ex. R Name H)⁺ (min.) ¹H NMR  61 

1-(2-hydroxy-2- methylpropyl)-5- metboxy- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)- 1H-indazole-3-carboxamide 502.3 E: 1.60 F: 1.61 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47(s, 1H), 8.32 (br d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.97-7.89 (m, 1H), 7.89-7.80 (m, 2H), 7.67 (br d, J = 9.2 Hz, 1H), 7.51 (s,1H), 7.05 (br d, J = 9.2 Hz, 1H), 4.47-4.35 m, 1H), 4.32 (s, 2H),3.94-3.85 (m, 2H), 3.79 (s, 3H), 2.67-2.53 (m, 2H), 2.45-2.29 (m, 4H),2.26-2.10 (m, 2H), 1.12 (s, 6H)  62 

1-(2-hydroxy-2- methylpropyl)-6- methoxy- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)- 1H-indazole-3-carboxamide 502.4 E: 1.62 F: 1.60 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 8.32 (br d, J = 7.9 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.01-7.93 (m, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.89-7.85 (m, 1H), 7.86-7.80 (m,1H), 7.21 (d, J = 1.2 Hz, 1H), 6.85 (dd, J = 8.9, 1.8 Hz, 1H), 4.40(sxt, J = 8.3 Hz, 1H), 4.32 (s, 2H), 3.95-3.85 (m, 1H), 3.83 (s, 3H),2.68-2.53 (m, 2H), 2.44-2.29 (m, 4H), 2.25-2.09 (m, 2H), 1.15 (s, 6H) 63 

6-methoxy-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-y1)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3- 430.5 E: 1.44 F:1.41 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.44 (br d, J = 5.5Hz, 2H), 8.25 (br t, J = 8.4 Hz, 2H), 8.07 (br d, J = 9.5 Hz, 1H),7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.79 (m., 1H), 7.24 (br d., J= 9.8 Hz, 1H), 4.42- 4.29 (m, 1H), 3.84 (s, 3H), 2.67-2.53 (m, 3H),2.44- 2.30 (m, 3H), 2.27-2.13 (m, 2H), 2.04 (br t, J = 10.1 Hz,carboxamide 1H)  64 

5-methoxy-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 430.4E: 1.40 F: 1.45 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H),8.64-8.53 (m, 1H), 8.50-8.38 (m, 1H), 8.30-8.13 (m, 2H), 7.96-7.85 (m,1H), 7.86-7.80 (m, 1H), 7.53-7.47 (m, 1H), 6.70 (dd. J = 7.5, 2.6 Hz,1H), 4.40-4.29 (m, 1H), 3.96-3.89 (m, 1H), 3.88-3.83 (m, 3H), 2.69-2.53(m, 2H), 2.44-2.32 (m, 2H), 2.28-2.16 (m, 2H), 2.09- 1.97 (m, 1H)  65 

5-fluoro-1-(2-hydroxy-2- methylpropyl)-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl- 1H-indazole-3-carboxamide 490.4 E: 1.65 F: 1.64 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 8.42 (br d, J = 7.9 Hz, 1H), 8.26 (ft J = 7.6 Hz, 1H), 7.97-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m, 2H), 7.76 (dd, J = 8.9,2.1 Hz, 1H), 7.33 (td, J = 9.1, 2.3 Hz, 1H), 4.46-4.39 (m, 1H), 4.38 (s,2H), 3.90 (quin, J = 8.5 Hz, 1H), 2.66-2.56 (m, 2H), 2.46-2.30 (m, 4H),2.26- 2.11 (m, 2H), 1.14 (s, 6H)  66 

1-(2-hydroxy-2- methylpropyl)-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)- 1H-pyrrolo[2,3-b]pyridine- 3-carboxamide 472.4 E: 1.33 F: 1.40 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 8.45 (d, J = 7.9 Hz, 1H), 8.31-8.17 (m, 4H), 7.95-7.90 (m, 1H),7.90- 7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.23-7.17 (m, 1H), 4.46-4.33 (m,1H.), 4.22 (s, 2H), 3.91 (quin, J = 8.5 Hz, 1H), 2.69-2.55 (m, 2H),2.44-2.32 (m, 3H), 2.28-2.18 (m, 2H), 2.06 (br t, J = 9.9 Hz, 1H), 1.07(s, 6H)  67 

6-(2-hydroxy-2- methylpropoxy)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- 488.4 E: 1.41 F: 1.38 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.46 (s, 1H), 8.48-8.40 (m, 2H), 8.24 (dd, J = 11.1, 8.1 Hz, 2H),8.08 (d, J = 9.5 Hz, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H),7.85-7.79 (m, 1H), 7.31-7.21 (m, 1H), 4.69 (s, yl)spiro[3.3]heptan-2-1H), 4.43-4.31 (m., 1H), 3.91 (quin, J = 8.5 Hz, 1H), 3.79yl)pyrazolo[1,5- (s, 2H), 2.68-2.56 (m, 2H), 2.45-2.34 (m, 3H), 2.29-a]pyridine-3- 2.16 (m, 2H), 2.04 (br t, J = 10.1 Hz, 1H), 1.22 (s, 6H)carboxamide  68 

6-(2-morpholinoethoxy)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- 529.5 E: 1.16 F: 1.34 ¹H NMR: (500 MHz DMSO-d₆) δppm 12.47 (s, 1H), 8.54 (br s, 1H), 8.47 (s, 1H), 8.26 (br d, J = 7.6Hz, 2H), 8.10 (br d, J = 9.5 Hz. 1H), 7.96-7.90 (m, 1H), 7.89- 7.86 (m,1H), 7.86-7.79 (m, 1H), 7.28 (br d, J = 9.8 Hz, yl)pyrazolo[1,5- 1H),4.42-4.33 (m, 1H), 4.35-4.20 (m, 1H), 3.91 (quin, a]pyridine-3- J = 8.5Hz, 1H), 2.68-2.59 (m, 1H), 2.54 (s, 4H), 2.45- carboxamide 2.32 (m,3H), 2.28-2.16 (m, 2H), 2.04 (br t, J = 10.1. Hz, 1H)  69 

2-morpholino-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)thiazole-5- carboxamide 452.4 E: 1.26 F:1.33¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.35 (br d, J = 7.6 Hz,1H), 8.26 (d, J = 7.9 Hz, 1H), 7.96- 7.90 (m, 1H), 7.89-7.79 (m, 3H),4.26 (sxt, J = 8.1 Hz, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 3.70 (t, J =4.9 Hz, 4H), 3.43 (t, J = 4.7 Hz, 2H), 2.65-2.55 (m, 2H), 2.43-2.30 (m,3H), 2.26-2.12 (m, 2H), 2.01 (t, J = 9.9 Hz, 1H)  70 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-2-(pyrrolidin-1-yl) thiazole- 5-carboxamide 436.4 E: 1.21 F: 1.44 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.45 (s, 1H), 8.28-8.21 (m, 2H),7.94-7.89 (m, 1H), 7.88-7.81 (m, 2H), 7.80 (s, 1H), 4.25 (sxt, J = 8.1Hz, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.65-2.54 (m, 2H), 2.42-2.30 (m,3H), 2.23-2.11 (m, 2H), 2.06-1.91 (m, 5H)  71 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)benzo[d]isoxazole-3- carboxamide 401.4 E: 1.73 F: 1.75 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 9.25 (br d, J = 7.6 Hz, 1H), 8.22 (brd, J = 7.6 Hz, 1H), 8.04 (br d, J = 7.9 Hz, 1H), 7.92-7.85 (m, 1H),7.85-7.76 (m, 3H), 7.69 (br t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.5 Hz,1H), 4.43-4.31 (m, 1H), 3.92-3.80 (m, 1H), 2.65-2.57 (m, 1H), 2.41-2.29(m, 4H), 2.25-2.17 (m, 1H), 2.16-2.07 (m, 1H)  72 

1-(2-hydroxy-2- methylpropyl)-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)- 1H-indole-3-carboxamide471.3 E: 1.52 F: 1.53 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.43 (s, 1H),8.22 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.05- 7.97 (m, 2H),7.91-7.82 (m, 2H), 7.82-7.76 (m, 1H), 7.52 (d, J = 8.2 Hz, 1H),7.14-7.08 (m, 1H), 7.07-7.00 (m, 1H), 4.40-4.29 (m, 1H), 4.04 (s, 2H),3.91-3.81 (m, 1H), 2.57 (br d, J = 11.6 Hz, 1H), 2.41-2.27 (m, 3H),2.23-2.12 (m, 2H), 2.01 (br t, J = 9.9 Hz, 1H), 1.06 (s, 6H)  73 

5-(2-morpholinoethoxy)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 529.3 E: 1.12 F: 1.35 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.45(s, 1H), 8.25 (br d, J = 7.6 Hz, 1H), 8.17 (br d, J = 7.3 Hz, 1H),7.96-7.78 (m, 3H), 7.52 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 7.3, 2.4 Hz,1H), 4.40- 4.28 (m, 1H), 4.17 (br t, J = 5.3 Hz, 2H), 3.96-3.84 (m,a]pyridine-3-carboxamide 1H), 3.61-3.52 (m, 4H), 2.74 (br t, J = 5.5 Hz,2H), 2.66- 2.57 (m, 1H), 2.43-2.31 (m, 3H), 2.29-2.14 (m, 2H), 2.04 (brt, J = 9.9 Hz, 1H)  74 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5- a]pyridine-3-carboxamide 400.2 E: 1.33 F: 1.34 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.76 (d, J = 7.0 Hz, 1H), 8.58(s, 1H), 8.31 (br d, J = 7.6 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.20 (s,1H), 7.98-7.88 (m, 2H), 7.87-7.80 (m, 1H), 7.51-7.40 (m, 1H), 7.06 (t, J= 6.9 Hz, 1H), 4.45-4.35 (m, 1H), 3.93 (quin, J = 8.3 Hz, 1H), 2.70-2.57(m, 2H), 2.47-2.34 (m, 3H), 2.31-2.18 (m, 2H), 2.11-2.02 (m, 1H)  75 

5-(2-hydroxy-3- methoxypropoxy)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 504.4 E:1.28 F: 1.30 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.58 (d, J = 7.3 Hz, 1H),8.45 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.20 (br d, J = 7.3 Hz, 1H),7.95-7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.49 (d, J = 2.7 Hz, 1H), 6.71(dd, J = 7.5, 2.6 Hz, 1H), 5.25 (d, J = 5.2 Hz, 1H), 4.38-4.27 (m, 1H),4.08-4.03 (m, 1H), 4.03-3.84 (m, 3H), 3.29 (s, 3H), 2.67-2.55 (m,a]pyridine-3-carboxamide 2H), 2.44-2.33 (m, 3H), 2.27-2.16 (m, 2H),2.08-1.98 (m, 1H)  76 

6-morpholino-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 485.2 E: 1.28 F: 1.28 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.41 (s, 1H), 8.25 (br d, J =7.7 Hz, 2H), 8.11 (s, 1H), 8.04 (d, J = 9.8 Hz, 1H), 7.96-7.90 (m, 1H),7.89-7.80 (m, 2H), 7.47 (br d, J = 9.4 Hz, 1H), 4.43-4.29 (m, 1H), 3.96-3.85 (m, 1H), 3.75 (br s, 4H), 3.09 (br s, 4H), 2.62 (br s,a]pyridine-3-carboxamide 1H), 2.43-2.31 (m, 3H), 2.26-2.15 (m, 2H), 2.03(br t, J = 10.0 Hz, 1H)  77 

5-(2-hydroxyethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 460.1E: 1.26 F: 1.24 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.44 (s, 1H), 8.52 (d,J = 7.3 Hz, 1H), 8.40 (s, 1H), 8.20 (br dd, J = 11.3, 7.6 Hz, 2H),7.92-7.85 (m, 1H), 7.85-7.75 (m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 6.68(dd, J = 7.6, 2.4 Hz, 1H), 4.35- 4.24 (m, 1H), 4.03 (br t, J = 4.6 Hz,2H), 3.86 (br t, J = 8.2 Hz, 1H), 3.72 (br s, 2H), 2.57 (br s, 2H),2.40-2.26 (m, 3H), 2.23-2.10 (m, 2H), 2.03-1.94 (m, 1H)  78 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)benzo[c]isoxazole-3- carboxamide 401.2 E: 1.52 F: 1.52 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.48 (br d, J = 7.5 Hz, 1H), 8.25 (brd, J = 7.7 Hz, 1H), 7.93 (br d, J = 10.3 Hz, 2H), 7.91-7.86 (m, 2H),7.86-7.81 (m, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.53-7.43 (m, 1H),7.32-7.22 (m, 1H), 4.43-4.34 (m, 1H), 3.94-3.85 (m, 1H), 2.63 (br s,1H), 2.44-2.31 (m, 4H), 2.25 (br s, 1H), 2.21-2.13 (m, 1H)  79 

6-(difluoromethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 466.2 E: 1.44 F: 1.44 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.89 (s, 1H), 8.59 (s, 1H), 8.40(br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.21 (d, J = 9.7Hz, 1H), 7.96-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.45 (br d, J = 9.6 Hz,1H), 7.26 (t, J = 73.4 Hz, 1H), 4.42-4.32 (m, 1H), 3.90 (quin,a]pyridine-3-carboxamide J = 8.5 Hz, 1H), 2.68-2.60 (m, 1H), 2.60-2.54(m, 1H), 2.44-2.31 (m, 3H), 2.28-2.17 (m, 2H), 2.04 (br t, i J = 10.0Hz, 1H)  80 

6-(2,2-difluoroethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 480.1 E: 1.53 F: 1.53 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.29(br d, J = 7.3 Hz, 1H), 8.25 (br d, J = 7.9 Hz, 1H), 8.10 (br d, J = 9.8Hz, 1H), 7.96- 7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.32 (br d, J = 9.8 Hz,1H), 6.42 (br t, J = 54.3 Hz, 1H), 4.49-4.30 (m, 3H), 3.95-a]pyridine-3-carboxamide 3.83 (m, 1H), 2.61 (br d, J = 12.2 Hz, 1H),2.44-2.30 (m, 3H), 2.28-2.16 (m, 2H), 2.08-1.99 (m, 1H)  81 

6-(2-(1H-pyrazo1-1- yl)theoxy)-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- 510.3 E: 1.11 F: 1.39 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.46 (br d, J = 11.0 Hz,2H), 8.26 (br t, J = 7.2 Hz, 2H), 8.05 (br d, J = 9.6 Hz, 1H), 7.95-7.89(m, 1H), 7.89- 7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.80 (s, 1H), 7.46 (s,1H), 7.18 (br d, J = 9.7 Hz, 1H), 6.25 (s, 1H), 4.52 (br d,yl)pyrazolo[1,5- J = 4.8 Hz, 2H), 4.41 (br t, J = 4.7 Hz, 2H), 4.38-4.31(m, a]pyridine-3-carboxamide 1H), 3.90 (br t, J = 8.4 Hz, 1H), 2.62 (brs, 1H), 2.44- 2.32 (m, 3H), 2.27-2.16 (m, 2H), 2.03 (br t, J = 10.0 Hz,1H)  82 

6-(4,4-difluoropiperidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 519.1 E:1.62 F: 1.63 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.42 (s,1H), 8.28-8.20 (m, 3H), 8.04 (d, J = 9.7 Hz, 1H), 7.94-7.90 (m, 1H),7.90-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.49 (br d, 19.8 Hz, 1H),4.42-4.32 (m, 1H), 3.90 (br t, J = 8.5 Hz, 1H), 2.62 (br s, 1H), 2.55(br d, J = 13.8 a]pyridine-3-carboxamide Hz, 1H), 2.44-2.33 (m, 3H),2.28-2.18 (m, 2H), 2.11 (br t, J = 13.6 Hz, 4H), 2.06-1.99 (m, 1H)  83 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(2-(pyrrolidin-1- yl)ethoxy)pyrazolo[1,5-a] 513.1 E: 1.01 F: 1.05 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.45 (br d, J = 6.2 Hz,2H), 8.26 (br t, J = 7.0 Hz, 2H), 8.07 (d, J = 9.6 Hz, 1H), 7.95-7.90(m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.25 (br d, J = 9.7 Hz,1H), 4.42- 4.31 (m, 1H), 4.12 (br t, J = 5.5 Hz, 2H), 3.90 (quin,pyridine-3-carboxamide J = 8.4 Hz, 1H), 2.81 (br t, J = 5.5 Hz, 2H),2.61 (br d, J = 11.1 Hz, 1H), 2.59-2.55 (m, 1H), 2.53 (br s, 4H), 2.44-2.31 (m, 3H), 2.27-2.17 (m, 2H), 2.04 (br t J = 10.0 Hz, 1H), 1.68 (brs, 4H)  84 

5-morpholino-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 485.2E: 1.26 F: 1.29 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.50 (d,J = 7.7 Hz, 1H), 8.38 (s, 1H), 8.25 (br d, J = 7.7 Hz, 1H), 8.08 (br d,J = 7.5 Hz, 1H), 7.96-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m,1H), 7.33 (s, 1H), 6.95-6.89 (m, 1H), 4.39-4.28 (m, 1H), 3.90 (quin, J =8.4 Hz, 1H), 3.76 (br s, 4H), 3.23 (br s, 4H), 2.65- 2.57 (m, 1H),2.43-2.33 (m, 3H), 2.26-2.16 (m, 2H), 2.07-1.98 (m, 1H), 2.02 (br t, J =10.0 Hz, 1H)  85 

5-(1-methyl-1H-pyrazol-4- yl)-N-((aR)-6-(4-oxo-3,4- dthydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 480.1E: 1.26 F: 1.27 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.72 (d,J = 7.2 Hz, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.30- 8.21 (m, 3H), 7.99(s, 1H), 7.95-7.90 (m, 1H), 7.90- 7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.27(br d, J = 7.2 Hz, H), 4.43-4.32 (m, 1H), 3.96-3.90 (m, 1H), 3.89 (s,3H), 2.64 (br s, 1H), 2.61-2.56 (m, 1H), 2.45-2.32 (m, 3H), 2.29-2.18(m, H), 2.06 (br t, J = 10.1 Hz, 1H)  86 

6-(4-methylpiperazin-1- yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- 498.3 E: 0.97 F: 1.08 ¹H NMR: (500 MHz DMSO-d₆) δppm 12.50 (s, 1H), 8.44 (s, 1H), 8.26 (br t, J = 8.0 Hz, 2H), 8.21 (brs, 1H), 8.06 (br d, J = 9.7 Hz, 1H), 7.96-7.91 (m, 1H), 7.90- 7.87 (m,1H), 7.87-7.82 (m, 1H), 7.48 (br d, J = 9.3 Hz, yl)pyrazolo[1,5- 1H),4.43-4.32 (m, 1H), 3.91 (q, J = 8.4 Hz, 1H), 3.37 (bra]pyridine-3-carboxamide s, 8H), 3.26 (br s, 3H), 2.93 (br s, 2H), 2.63(br s, 1H), 2.44-2.32 (m, 1H), 2.29-2.16 (m, 2H), 2.05 (br t, J = 10.0Hz, 1H)  87 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(pyrrolidin-1- yl)pyrazolo[1,5- 469.3 E: 1.52 F: 1.60 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.32 (s, 1H), 8.25 (br d, J = 7.7 Hz,1H), 8.15 (br d, J = 7.6 Hz, 1H), 8.01 (d, 1-9.5 Hz, 1H), 7.95-7.90 (m,1H), 7.90-7.86 (m, 1H), 7.86-7.82 (m, 1H), 7.80 (s, 1H), 7.18 (br d, J =).6 Hz, 1H), 4.41-4.32 (m, 1H), 3.90 a]pyridine-3-carboxamide (quin, J =8.4 Hz, 1H), 2.62 (br s, 1H), 2.59-2.52 (m, 1H), 2.44-2.31 (m, 3H),2.27-2.15 (m, 2H), 2.03 (br t, J = 10.0 Hz, 1H), 1.96 (br s, 4H)  88 

6-((R)-3-fluoropyrrolidin- 1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- 487 E: 1.43 F: 1.45 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.35 (s, 1H), 8.25 (br d, J= 7.7 Hz, 1H), 8.17 (br d, J = 7.5 Hz, 1H), 8.04 (br d, J = 9.6 Hz, 1H),7.97-7.86 (m, 3H), 7.86-7.80 (m, 1H), 7.22 (br d, J = 9.6 Hz, 1H), 5.47(br d, yl)pyrazolo[1,5- J = 54.9 Hz, 1H), 4.42-4.30 (m, 1H), 3.96-3.85(m, 1H), a]pyridine-3-carboxamide 3.63-3.51 (m, 1H), 2.61 (br d, J =11.5 Hz, 1H), 2.45- 2.32 (m, 3H), 2.30-2.14 (m, 4H), 2.04 (br t, J =10.0 Hz, 1H)  89 

6-((S)-3-fluoropyrrolidin- 1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- 487.2 E: 1.43 F: 1.46 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.35 (s, 1H), 8.25 (br d, J= 7.8 Hz, 1H), 8.17 (br d, J = 7.6 Hz, 1H), 8.04 (d, J = 9.6 Hz, 1H),7.97-7.86 (m, 3H), 7.86-7.81 (m, 1H), 7.22 (br d, J = 9.6 Hz, 1H), 5.46(br d, yl)pyrazolo[1,5- J = 53.0 Hz, 1H), 4.42-4.31 (m, 1H), 3.95-3.85(m, 1H), a]pyridine-3-carboxamide 3.61-3.51 (m, 1H), 2.61 (br d, J =11.8 Hz, 1H), 2.45- 2.32 (m, 3H), 2.30-2.14 (m, 4H), 2.03 (br t, J =10.0 Hz, 1H)  90 

6-(3,3-difluoropyrrolidin- 1-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 505.3E: 1.53 F: 1.56 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.38 (s,1H), 8.25 (br d, J = 7.7 Hz, 1H), 8.20 (br d, J = 7.6 Hz, 1H), 8.05 (d,J = 9.6 Hz, 1H), 8.00 (s, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H),7.86-7.81 (m, 1H), 7.25 (br d, J = 9.5 Hz, 1H), 4.42-4.31 (m, 1H), 3.90(quin, a]pyridine-3-carboxamide J = 8.4 Hz, 1H), 3.73 (br t, J = 13.2Hz, 2H), 3.51 (br t, J = 7.1 Hz, 1H), 2.62 (br s, 1H), 2.59-2.52 (m,3H), 2.44- 2.3 (m, 3H), 2.27-2.16 (m, 2H), 2.04 (br t, J = 10.0 Hz, 1H) 91 

6-(3-fluoroazetidin-1-yl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- 473.2 E: 1.36 F: 1.39 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.38 (s, 1H), 8.25 (br d, J =7.7 Hz, 1H), 8.20 (br d, J = 7.5 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H),7.95-7.89 (m, 2H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.00 (br d, J =9.4 Hz, 1H), 5.49 (br d, J = 57.4 Hz, 1H), 4.42-4.30a]pyridine-3-carboxamide (m, 1H), 4.24-4.12 (m, 2H), 3.95 (br d, J = 9.3Hz, 1H), 3.89 (br d, J = 8.1 Hz, 2H), 2.61 (br d, J = 11.6 Hz, 1H),2.44-2.30 (m, 3H), 2.27-2.16 (m, 2H), 2.03 (br t, J = 10.0 Hz, 1H)  92 

6-(3,3-difluoroazetidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 491.3 E: 1.46 F: 1.49 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.41 (s, 1H), 8.24 (br t, J = 8.7 Hz, 2H),8.11-8.03 (m, 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.80 (m, 1H),7.06 (br d, J = 9.5 Hz, 1H), 4.33 (br t, J = 12.2 Hz, 4H), 3.94-3.86 (m,1H), 2.61 (br d, J = 11.3 Hz, 1H), 2.57 (br s, 1H), 2.45-2.32 (m, 3H),2.27-2.16 (m, 2H), 2.04 (br t, J = 10.1 Hz, 1H)  93 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)benzo[d]imidazo[2,1-b] thiazole-2-carboxamide 455.9 E: 1.73 F: 1.74¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.39 (br d, J = 7.9 Hz,1H), 8.25 (br d, J = 7.9 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.04 (d, J =7.9 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.79 (m, 1H),7.60-7.54 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 4.42-4.30 (m, 1H), 3.89 (brt, J = 8.4 Hz, 1H), 2.63-2.52 (m, 3H), 2.44-2.35 (m, 2H), 2.35-2.26 (m,2H), 2.19 (br d, J = 6.4 Hz, 1H), 2.15- 2.08 (m, 1H)  94 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)benzo[d]imidazo[2,1-b] thiazole-2-carboxamide 455.9 E: 1.73 F: 1.74¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.39 (br d, J = 7.9 Hz,1H), 8.25 (br d, J = 7.9 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.04 (d, J =7.9 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.79 (m, 1H),7.60-7.54 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 4.42-4.30 (m, 1H), 3.89 (brt, J = 8.4 Hz, 1H), 2.63-2.52 (m, 3H), 2.44-2.35 (m, 2H), 2.35-2.26 (m,2H), 2.19 (br d, J = 6.4 Hz, 1H), 2.15- 2.08 (m, 1H)  95 

2-ethyl-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[2,1-b] [1,3,4]thiadiazole-6-carboxamide 435 E: 1.57 F: 1.57 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 8.49 (s, 1H), 8.32 (br d, J = 7.9 Hz, 1H), 8.25 (br d, J = 7.9Hz, 1H), 7.96-7.89 (m, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.85-7.78 (m, 1H),4.39-4.28 (m, 1H), 3.88 (br t, J = 8.2 Hz, 1H), 3.09 (q, J = 7.5 Hz,2H), 2.54 (br s, 2H), 2.42- 2.23 (m, 4H), 2.18 (br s, 1H), 2.13-2.05 (m,1H), 1.33 (br t, J = 7.3 Hz, 3H)  96 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5- b]pyridazine-3- carboxamide 401.1 E: 1.12 F: 1.12 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.68-8.60 (m, 2H), 8.58 (brs, 1H), 8.53 (br d, J = 7.4 Hz 1H), 8.25 (br d, J = 7.8 Hz, 1H),7.96-7.90 (m, 1H), 7.90- 7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.41 (dd. J =8.9, 4.3 Hz, 1H). 4.43-4.31 (m, 1H), 3.91 (br t, J = 8.5 Hz, 1H), 2.64(br s, 1H), 2.60-2.56 (m, 1H), 2.45-2.32 (m, 3H), 2.30-2.18 (m, 2H)  97 

7-cyclopropyl-6-(2- hydroxy-2- methylpropoxy)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- 528.3 E: 1.61 F: 1.55 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.49 (s, 1H), 8.51 (s, 1H), 8.32-8.20 (m, 2H), 8.03 (d, J = 9.6 Hz,1H), 7.96-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.46 (d, J= 9.8 Hz, 1H), 4.71 (br s, 1H), 4.44-4.28 (m, 1H), 3.90 (quin, J = 8.3Hz, 1H), 3.78 (s, 2H), 2.69- yl)spiro[3.3]heptan-2- 2.55 (m, 3H),2.44-2.30 (m, 3H), 2.27-2.16 (m, 2H), yl)pyrazolo[1,5- 2.04 (br t, J =10.1 Hz, 1H), 1.48 (br d, J = 3.8 Hz, 2H), a]pyridine-3-carboxamide 1.23(s, 6H), 1.05 (br dd, J = 8.6, 2.1 Hz, 2H)  98 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3,3,3-trifluoro-2- hydroxy-2- 596.3 E: 1.78 F: 1.82 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.69 (s, 1H), 8.49 (s, 1H), 8.27 (br t, J= 9.2 Hz, 2H), 8.12 (br d, J = 9.8 Hz, 1H), 7.96-7.90 (m, 1H), 7.90-7.86(m, 1H), 7.86-7.79 (m., 1H), 7.27 (br d, J = 9.5 Hz, 1H), 4.51 (s, 2H),4.42-4.32 (m, 1H), 2.63 (br s, 1H), 2.46-2.32 (trifluoromethyl)propoxy)(m, 3H), 2.29-2.16 (m, 2H), 2.05 (br t, J = 10.1 Hz, 1H)pyrazolo[1,5-a]pyridine-3- carboxamide  99 

6-(benzyloxy)-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- 506.1 E: 1.79 F: 1.79 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.49 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.28 (br d, J = 7.5 Hz,1H), 8.25 (br d, J = 7.9 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.96-7.90(m, 1H), 7.90-7.86 (m, 1H), 7.86-7.78 (m, 1H), 7.49 yl)pyrazolo[1,5- (brd, J = 7.4 Hz, 2H), 7.41 (br t, J = 7.4 Hz, 2H), 7.38-a]pyridine-3-carboxamide 7.34 (m, 1H), 7.32 (br d, J = 9.6 Hz, 1H), 5.16(s, 2H), 4.43-4.30 (m, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.62 (br t, J =11.7 Hz, 1H), 2.44-2.31 (m, 3H), 2.27-2.15 (m, 2H), 2.04 (br t, J = 10.0Hz, 1H) 100 

1-(2,2-difluoroethyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-pyrazole-5- carboxamide 414.2 E: 1.42 F:1.42 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.73 (br d, J = 7.5Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.95- 7.88 (m, 1H), 7.86 (d, J = 9.3Hz, 2H), 7.84-7.79 (m, 1H), 7.58 (s, 1H), 6.95 (s, 1H), 6.31 (br t, J =55.5 Hz, 1H), 5.04-4.86 (m, 2H), 4.36-4.21 (m, 1H), 3.89 (quin, J = 8.4Hz, 1H), 2.60 (br s, 1H), 2.43-2.30 (m, 3H), 2.22 (br t, J = 9.4 Hz,2H), 2.04 (br t, J = 10.0 Hz, 1H) 101 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1-(3,3,3-trifluoropropyl)- 1H-pyrazole-5- carboxamide 446.2 E: 1.60 F:1.60 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.66 (br d, J = 7.3Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.96- 7.90 (m, 1H), 7.89-7.78 (m,2.H), 7.52 (s, 1H), 6.91 (s, 1H), 4.73 (br t, J = 6.9 Hz, 2H), 4.37-4.22(m, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.86-2.73 (m, 2H), 2.66-2.57 (m,1H), 2.44-2.30 (m, 3H), 2.21 (br t, J = 9.8 Hz, 2H), 2.04 (br t, J =10.0 Hz, 1H) 102 

1-(4-methoxybenzyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl- 1H-pyrazole-4- carboxamide 470.1 E: 1.49 F:1.49 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.24 (br d. J = 7.8Hz, 1H), 8.19 (br d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.95-7.89 (m, 1H),7.88-7.77 (m, 3H), 7.22 (br d, J = 8.4 Hz, H), 6.91 (br d, J = 8.4 Hz,2H), 5.23 (s, 2H), 4.32-4.20 (m, 1H), 3.87 (quin, J = 8.5 Hz, 1H), 3.72(s, 3H), 2.59 (br s, 1H), 2.42-2.27 (m, 3H), 2.22-2.07 (m, 2H), 1.96 (brt, J = 10.0 Hz, 1H) 103 

1-(eyclopropylmethyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-pyrazole-5- carboxamide 404.3 E: 1.51 F:1.51 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.61 (br d, J = 7.3Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.95- 7.89 (m, 1H), 7.88-7.80 (m,2.H), 7.45 (s, 1H), 6.83 (s, 1H), 4.32 (br d, J = 7.1 Hz, 2H), 4.30-4.20(m, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 2.68-2.58 (m, 1H), 2.45-2.29 (m,3H), 2.21 (br t, J = 9.6 Hz, 2H), 2.09-1.99 (m, 1H), 1.21 (br d, J = 7.1Hz, 1H), 0.40 (br d., J = 7.2 Hz, 2H), 0.30 (br d, J = 4.3 Hz, 2H) 104 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1-(tetrahydro-2H-pyran-4- yl)-1H-pyrazole-5- carboxamide 434.3 E: 1.36F: 1.36 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.62 (br d, J =7.6 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.97- 7.89 (m, 1H), 7.88-7.78 (m,2H), 7.50 (s, 1H), 6.82 (s, 1H), 5.29 (br t, J = 11.5 Hz, 1H), 4.36-4.23(m, 1H), 3.94. (br d, J = 10.9 Hz, 2H), 3.89 (br t, J = 8.4 Hz, 1H),3.40 (br t, J = 11.9 Hz, 2H), 2.59 (br s, 1H), 2.43-2.28 (m, 3H), 2.21(br t, J = 9.4 Hz, 2H), 2.08-1.94 (m, 3H), 1.79 (br d, J = 11.3 Hz, 2H)105 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a] 486.2 E: 1.41 F: 1.41 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.45 (br s, 2H), 8.28 (brd, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.08 (d, J = 9.6 Hz,1H), 7.97-7.90 (m, 1H), 7.89-7.85 (m, 2H), 7.85-7.77 (m, 1H), 7.24 (brd, J = 9.6 Hz, 1H), 5.08 (br s, 1H), 4.43-4.29 (m, 1H), 3.96-pyridine-3-carboxamide 3.81 (m, 4H), 3.80-3.70 (m, 1H), 2.67-2.58 (m,1H), 2.44-2.31 (m, 3H), 2.31-2.15 (m, 3H), 2.09-1.96 (m, 2H) 106 

tert-butyl (2-(4-(((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)carbamoyl)-1H-pyrazol- 1-yl)ethyl)carbamate493 E: 1.34 F: 1.33 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25(d, J = 7.7 Hz, 1H), 8.16 (br d, J = 7.3 Hz, 1H), 8.07 (s, 1H),7.95-7.89 (m, 1H), 7.88-7.79 (m, 3H), 6.92 (br s, 1H), 4.33-4.23 (m,1H), 4.12 (br t, J = 5.8 Hz, 2H), 3.89 (quin, J = 8.4 Hz, 1H), 3.28 (brd, J = 5.9 Hz, 1H), 2.64-2.55 (m, 1H), 2.43-2.29 (m, 3H), 2.24-2.17 (m,1H), 2.18-2.09 (m, 1H), 1.34 (s, 9H) 107 

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl-6-(3,3,3-trifluoro-2- hydroxypropoxy)pyrazolo 528.1 E: 1.44 F: 1.39 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 8.52 (s, 1H), 8.42 (s, 1H), 8.27 (br d, J= 7.5 Hz, 1H), 8.21 (br d, J = 7.8 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H),7.91-7.84 (m, 1H), 7.84-7.74 (m, 2H.), 7.23 (br d, J = 9.7 Hz, 1H), 4.40(br d, J = 3.5 Hz, 1H), 4.37-4.27 (m, 1H), 4.22 (br dd, J = 10.5,[1,5-a]pyridine-3- 3.2 Hz, 1H), 4.11 (br dd, J = 10.3, 6.6 Hz, 1H), 3.84(quin, carboxamide J = 8.4 Hz, 1H), 3.49 (br s, 2H), 2.62-2.55 (m, 1H),2.40- 2.26 (m, 3H), 2.23-2.12 (m, 2H), 1.99 (br t, J = 10.0 Hz, 1H) 108 

1-(3-methoxyphenyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-pyrazole-4- carboxamide 456.3 E: 1.62 F:1.61 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.90 (s, 1H), 8.37(br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.7 Hz, 1H), 8.12 (s, 1H),7.96-7.89 (m, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.85-7.79 (m, 1H),7.47-7.34 (m, 3H), 4.39- 4.25 (m, 1H), 3.89 (br t, J = 8.3 Hz, 1H), 3.82(s, 3H), 2.63 (br s, 1H), 2.44-2.29 (m, 3H), 2.23 (br s, 1H), 2.21- 2.13(m, 1H), 2.01 (br t, J = 9.8 Hz, 1H) 109 

1-benzyl-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-pyrazole-4- carboxamide 440.1 E: 1.54 F:1.58 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.25 (br d, J = 7.6Hz, 1H), 8.21 (s, 1H), 8.17 (br d, J = 7.0 Hz, 1H), 7.90 (br d, J = 7.3Hz, 1H), 7.88-7.76 (m, 3H), 7.35 (br d, J = 7.0 Hz, 2H), 7.31 (br d, J =6.7 Hz, 1H), 7.24 (br d, J = 7.0 Hz, 2H), 5.33 (s, 2H), 4.33-4.21 (m,1H), 3.88 (br t, J = 8.1 Hz, 1H), 2.56 (br s, 1H), 2.42-2.29 (m, 3H),2.19 (br s, 1H), 2.17-2.10 (m, 1H) 1.97 (br t, J = 10.1 Hz, 1H) 110 

6-(2-hydroxy-2- methylpropoxy)-N₃-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- 531.3 E: 1.16 F: 1.15 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.52 (s, 1H), 8.33 (br d, J= 7.5 Hz, 1H), 8.29-8.21 (m, 2H), 8.17 (br d, J = 9.8 Hz, 1H), 8.03 (brs, 1H), 7.96- 7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.58(br d, J = 9.8 Hz, 1H), 4.45-4.31 (m, 1H), 3.97- yl)pyrazolo[1,5- 3.87(m, 2H), 3.84 (s, 2H), 2.45-2.32 (m, 4H), 2.29- a]pyridine-3,7- 2.18 (m,2H), 2.04 (br t, J = 10.0 Hz, 1H), 1.19 (s, 6H) dicarboxamide 111 

7-cyano-6-hydroxy-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 441 E:1.31 F: 0.97 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (br s, 1H),8.29-8.23 (m, 2H), 8.22 (br d, J = 6.8 Hz, 1H), 7.97 (br d, J = 9.5 Hz,1H), 7.95-7.87 (m, 2H), 7.84 (br d, J = 7.4 Hz, 1H), 6.88 (br d, J = 9.3Hz, 1H), 4.34 (br d, J = 7.2 Hz, 1H), 3.90 (br t, J = 8.3 Hz, 1H),2.44-2.30 (m, 4H), 2.21 (br d, J = 8.8 Hz, 2H), 2.03 (br t, J = 9.7 Hz,1H) 112 

6-(2-hydroxy-2- methylpropoxy)-7-methyl- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- 501.9 E: 1.52 F: 1.57 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.47 (s, 1H), 8.55 (s, 1H), 8.26 (br d, J = 7.6 Hz, 2H), 8.07 (d, J= 9.5 Hz, 1H), 7.95-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.86- 7.80 (m, 1H),7.51 (d, J = 9.8 Hz, 1H), 4.45-4.32 (m, yl)spiro[3.3]heptan-2- 1H), 3.91(quin, J = 8.4 Hz, 1H), 3.80 (s, 2H), 2.65 (s, yl)pyrazolo[1,5- 3H),2.63-2.56 (m, 2H), 2.44-2.33 (m, 3H), 2.27-2.17 a]pyridine-3-carboxamide(m, 2H), 2.09-2.00 (m, 1H), 1.24 (s, 6H) 113 

6-(2-hydroxy-- methylpropoxy)-7- (methoxymethyl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- 532.1 E: 1.47 F: 1.52 ¹HNMR: (500 MHz DMSO-d₆) δ ppm 12.47 (s, 1H), 8.53 (s, 1H), 8.30 (br d, J= 7.6 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 9.8 Hz, 1H),7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.56 (d, J =9.8 Hz, 1H), 4.96 (s, 2H), 4.43-4.32 (m, 1H), 3.95-3.87 (m, 1H), 3.85(s, 2H), 2.63 (br t, J = 11.6 Hz, 1H), 2.57 (br yl)pyrazolo[1,5- s, 1H),2.54 (s, 3H), 2.45-2.33 (m, 3H), 2.29-2.18 (m, a]pyridine-3-carboxamide2H), 2.05 (br t, J = 10.1 Hz, 1H), 1.24 (s, 6H) 114 

5-methyl-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl- 1-phenyl-1H-1,2,3- triazole-4-carboxamide404.9 E: 1.70 F: 1.70 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H),8.73 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.94- 7.89 (m, 1H),7.88-7.85 (m, 1H), 7.85-7.79 (m, 1H), 7.68-7.57 (m, 5H), 4.37 (sxt, J =8.2 Hz, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.63-2.52 (m, 2H), 2.49 (br s,3H), 2.44- 2.29 (m, 4H), 2.24-2.10 (m, 2H) 115 

1-(4-methoxyphenyl)-5- methyl-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-1,2,3-triazole-4- carboxamide 471 E: 1.73F: 1.72 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 8.70 (br d, J =7.9 Hz, 1H), 8.25 (br d, J = 7.6 Hz, 1H), 7.97- 7.90 (m, 1H), 7.90-7.86(m, 1H), 7.86-7.77 (m., 1H), 7.52 (br d, J = 8.9 Hz, 2H), 7.15 (br d, J= 8.9 Hz, 2H), 4.43- 4.30 (m, 1H), 3.95-3.87 (m, 1H), 3.85 (s, 3H),2.64- 2.55 (m, 2H), 2.44-2.29 (m, 5H), 2.25-2.10 (m, 2H) 116 

1-(3-methoxyphenyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-1,2,3-triazole-4- carboxamide 456.9 E:1.71 F: 1.70 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.29 (s,1H), 8.83 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.95-7.90 (m,1H), 7.89-7.86 (m, 1H), 7.86-7.79 (m, 1H), 7.60-7.44 (m, 3H), 7.08 (brd, J = 7.9 Hz, 1H), 4.46-4.34 (m, 1H), 3.89 (t, J = 8.5 Hz, 1H), 3.86(s, 3H), 2.65-2.53 (m, 2H), 2.45-2.29 (m, 4H), 2.25-2.19 (m, 1H),2.18-2.11 (m, 1H) 117 

1-(2-methoxyphenyl)-5- methyl-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-1,2,3-triazole-4- carboxamide 471 E: 1.71F: 1.71 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.70 (br d, J =7.9 Hz, 1H), 8.25 (d. J = 7.6 Hz, 1H), 7.96- 7.89 (m, 1H), 7.89-7.85 (m,1H), 7.85-7.79 (m, 1H), 7.63 (br t, J = 7.9 Hz, 1H), 7.45 (d, J = 6.4Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 4.44-4.31(m, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 3.79 (s, 3H), 2.63-2.52 (m, 2H),2.44-2.32 (m, 4H), 2.30 (s, 3H), 2.25-2.11 (m, 2H) 118 

5-(4-fluorophenyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1,2,4-oxadiazole-3- carboxamide 445.9 E: 1.74F: 1.74 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.28 (br d, J =7.6 Hz, 1H), 8.29-8.20 (m, 3H), 7.96- 7.89 (m, 1H), 7.89-7.86 (m, 1H),7.85-7.80 (m, 1H), 7.52 (br t, J = 8.9 Hz, 2H), 4.40-4.30 (m, 1H), 3.90(quin, J = 8.4 Hz, 1H), 2.66-2.56 (m, 2H), 2.44-2.30 (m, 4H), 2.27-2.20(m, 1H), 2.19-2.12 (m, 1H) 119¹

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3,3,3-trifluoro-2- 528.1 E: 1.54 F: 1.60 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.47 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.32-8.22 (m, 2H), 8.10(d, J = 9.5 Hz, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.79 (m,1H), 7.27 (br d, J = 9.5 Hz, 1H), 4.44 (br d, hydroxypropoxy)pyrazolo J= 4.0 Hz, 1H), 4.40-4.31 (m, 1H), 4.28 (dd, J = 10.4, 3.7[1,5-a]pyridine-3- Hz, 1H), 4.16 (dd, J = 10.7, 6.4 Hz, 1H), 3.91 (br t,J = 8.4 carboxamide Hz, 1H), 2.68-2.60 (m, 1H), 2.60-2.54 (m, 1H), 2.45-2.31 (m, 3H), 2.29-2.17 (m, 2H), 2.11-1.99 (m, 1H) 120¹

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3,3,3-trifluoro-2- 528.1 E: 1.56 F: 1.60 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.47 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.32-8.22 (m, 2H), 8.10(d, J = 9.5 Hz, 1H), 7.95-7.90 (m, 1H, 7.90-7.86 (m, 1H), 7.86-7.79 (m,1H), 7.27 (br d, J = 9.5 Hz, 1H), 4.44 (br d, hydroxypropoxy)pyrazolo J= 4.0 Hz, 1H), 4.40-4.31 (m, 1H), 4.28 (dd, J = 10.4, 3.7[1,5-a]pyridine-3- Hz, 1H), 4.16 (dd, J = 10.7, 6.4 Hz, 1H), 3.91 (br t,J = 8.4 carboxamide Hz, 1H) 2.68-2.60 (m, 1H), 2.60-2.54 (m, 1H), 2.45-2.31 (m, 3H), 2.29-2.17 (m, 2H), 2.11-1.99 (m, 1H) 121²

N-((R)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a] pyridine-3-carboxamide486.1 E: 1.48 F: 1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H),8.46 (s, 2H), 8.25 (br d, J = 7.6 Hz, 2H), 8.08 (br d, J = 9.5 Hz, 1H),7.96-7.90 (m, 1H), 7.90-7.86 (m, 2H), 7.86- 7.79 (m, 1H), 7.24 (br d, J= 9.5 Hz, 1H), 5.09 (br s, 1H), 4.43-4.31 (m, 1H), 3.96-3.81 (m, 4H),3.80-3.70 (m, 1H), 2.45-2.32 (m, 4H), 2.30-2.16 (m, 4H) 122²

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5- a]pyridine-3-carboxamide486.1 E: 1.48 F: 1.54 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (br s, 1H),8.47 (br s, 2H), 8.27 (br d, J = 7.0 Hz, 2H), 8.10 (br d, J = 9.5 Hz,1H), 7.99-7.75 (m, 3H), 7.26 (br d, J = 9.8 Hz, 1H), 5.11 (br s, 1H),4.38 (br d, J = 7.9 Hz, 1H), 3.98- 3.82 (m, 4H), 3.78 (br d, J = 4.6 Hz,1H), 2.46-2.33 (m, 4H), 2.32-2.15 (m, 4H), 2.12-1.97 (m, 2H) ¹Example119 (peak 1; RT 19.06 min) and Example 120 (peak 2; RT 26.17 min) wereobtained via chiral separation of Example 107 under the followingconditions: column: Chiralpak ID, 21 × 250 mm, 5 μ; Mobile Phase: 45%MeOH/55% CO₂; flow conditions: 45 mL/min, 100 Bar, 40° C.; detectorwavelength: 220 nm; injection details: 0.5 mL injections. ²Example 121(peak 1; RT 27.80 min) and Example 122 (peak 2; RT 32.73 min) wereobtained via chiral separation of Example 105 under the followingconditions: column: Chiralpak IC, 21 × 250 mm, 5 μ; Mobile Phase: 50%MeOH/50% CO₂; flow conditions: 55 mL/min, 150 Bar, 40° C.; detectorwavelength: 220 nm; injection details: 0.5 mL injections.

Example 123:7-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Intermediate 2, HCl (10 mg, 0.034 mmol) was suspended in anhydrous PhMe(1 mL), then trimethylaluminum (2 M in PhMe) (0.051 mL, 0.103 mmol) wasadded dropwise (CAUTION: methane gas evolution occurs). After stirringfor 5 min at rt (clear solution obtained), ethyl7-methylpyrazolo[1,5-a]pyridine-3-carboxylate (9.10 mg, 0.045 mmol) wasadded, and the reaction mixture was stirred at 120° C., for 30 min undermicrowave irradiation. The reaction mixture was cooled to rt, andcarefully quenched with TFA (CAUTION: dropwise addition). The reactionmixture was diluted with MeOH, then solvent was removed under reducedpressure, the residue was diluted with DMF, filtered, and purified bypreparative HPLC to afford Example 123 (6.8 mg, 48% yield). MS(ESI) m/z:414.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.60 (s,1H), 8.33 (br d, J=7.5 Hz, 1H), 8.25 (br d, J=7.9 Hz, 1H), 8.10 (br d,J=8.8 Hz, 1H), 7.95-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H),7.43-7.35 (m, 1H), 6.96 (br d, J=6.8 Hz, 1H), 4.42-4.32 (m, 1H), 3.90(br t, J=8.3 Hz, 1H), 2.69 (s, 3H), 2.66-2.59 (m, 1H), 2.44-2.32 (m,3H), 2.29-2.17 (m, 2H), 2.04 (br t, J=9.9 Hz, 1H). HPLC RT=E: 1.39 F:1.31.

The following Examples in Table 7 were prepared by using a similarprocedure as shown in Example 123 by reacting Intermediate 2 with theappropriate esters.

TABLE 7 HPLC Meth- LCMS od, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 124

3-methoxy-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2- yl)imidazo[1,2-a] pyridine-2- carboxamide 430.2E: 1.01 F: 1.38 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, H), 8.37 (brd, J = 8.2 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.21 (br d, J = 6.9 Hz,1H), 7.95-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.47 (d, J= 9.3 Hz, 1H), 7.31-7.23 (m, 1H), 6.95 (t, J = 6.7 Hz, 1H), 4.43-4.32(m, 1H), 4.13 (s, 3H), 3.89 (quin, J = 8.4 Hz, 1H), 2.61-2.55 (m, 2H),2.36 (dt,. J = 36.0, 10.1 Hz, 4H), 2.23-2.16 (m, 1H), 2.16- 2.10 (m, 1H)125

6-(benzyloxy)-7- cyclopropyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3] heptan- 546.4 E: 2.01 F: 2.07 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.50 (s, 1H), 8.51 (s, 1H), 8.29 (br d, J = 7.2 Hz, 1H), 8.25 (brd, J = 7.9 Hz, 1H), 8.03 (d, J = 9.6 Hz, 1H), 7.96-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.79 (m, 1H), 7.57 (d, 1.9.7 Hz, 1H), 7.46 (br d, J =7.4 Hz, 2H), 7.43-7.38 (m, 4H), 7.37-7.30 (m, 1H), 5.15 (s, 2H),4.42-4.31 (m, 1H), 3.90 (quin, 2-yl)pyrazolo[1,5- J = 8.4 Hz, 1H), 2.61(br d,, J = 1.1.5 Hz, 1H), 2.43-2.31 (m, a]pyridine-3- 3H), 2.27-2.15(m, 2H), 2.03 (br t, J = 10.0 Hz, 1H), 1.37 carboxamide (br d, J = 3.6Hz, 2H), 1.02 (br d, J = 6.7 Hz, 2H) 126

6-(benzyloxy)-7- methyl- N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1-520.2 E: 1.87 F: 1.90 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),8.54 (s, 1H), 8.30 (br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H),8.07 (br d, J = 9.5 Hz, 1H), 7.97-7.89 (m, 1H), 7.89- 7.86 (m, 1H),7.86-7.80 (m, 1H), 7.62 (d. J = 9.7 Hz, 1H), 7.46 (br d, J = 7.3 Hz,2H), 7.39 (t. J = 7.0 Hz, 2H), 7.36- yl)spiro[3.3] 7.27 (m, 1H), 5.1.9(s, 2H), 4.43-4.30 (m, 1H), 3.90 (quin, heptan-2- J = 8.4 Hz, 1H), 2.62(br s, 1H), 2.58 (s, 3H), 2.43-2.32 yl)pyrazolo[1,5- (m, 3H), 2.25-2.14(m, 2H), 2.04 (br t, J = 10.0 Hz, 1H) a]pyridine-3- carboxamide 127

6-(benzyloxy)-7- cyano-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)pyrazolo[1,5- 531.1 E: 1.90 F: 1.95 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.62 (s, 1H), 8.49 (br d, J =7.3 Hz, 1H), 8.44 (br d, J = 9.8 Hz, 1H), 8.25 (br d, J = 7.9 Hz, 1H),7.96-7.89 (m, 1H), 7.89- 7.85 (m, 1H), 7.85-7.75 (m, 2H), 7.53-7.47 (m,2H), 7.43 (t, J = 6.9 Hz, 2H), 7.38 (br d, J = 6.7 Hz, 1H), 5.46 (s,2H), 4.42-4.30 (m, 1H), 3.91 (br t, J = 8.5 Hz, 1H), 2.64 a]pyridine-3-(br s, 1H), 2.57 (br s, 1H), 2.43-2.32 (m, 3H), 2.28-2.16 carboxamide(m, 2H), 2.09-2.00 (m, 1H) 128

7-cyclopropyl-6- hydroxy- N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)pyrazolo[1,5- a]pyridine-3- 456.3 E: 1.40 F:1.36 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.42 (s, 1H), 8.25(d, J = 7.8 Hz, 1H), 8.20 (br d, J = 7.7 Hz, 1H), 7.94-7.89 (m., 2H),7.89-7.86 (m, 1H), 7.85-7.79 (m, 1H), 7.16 (d, J = 9.5 Hz, 1H),4.41-4.30 (m, 1H), 3.95- 3.84 (m, 1H), 2.61 (br t, J = 1.1.6 Hz, 1H),2.47-2.40 (m, 2H), 2.40-2.32 (m, 3H), 2.27-2.15 (m, 2H), 2.03 (br t, J =10.0 Hz, 1H), 1.40-1.33 (m., 2H), 1.04-0.96 (m, 2H) carboxamide 129

1-(2-methoxy- phenyl)- N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)- 1H-1,2,3-triazole-4- carboxamide 457.3 E:1.62 F: 1.64 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.87- 8.77(m, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.97-7.90 (m, 1H), 7.90-7.86 (m, 1H),7.86-7.80 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.33 (d,J = 8.3 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.37 (sxt, J = 8.1 Hz, 1H),3.89 (t, J = 8.5 Hz, 1H), 3.85 (s, 3H), 2.65-2.55 (m, 2H), 2.43- 2.29(m, 4H), 2.25-2.17 (m, 1H), 2.17-2.08 (m, 1H) 130

6-(benzyloxy)-7- ((dimethylamino) methyl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)pyrazolo[1,5- 563.1 E:1.38 F: 1.48 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.64 (s,1H), 8.44 (br d, J = 7.6 Hz, 1H), 8.32 (d, J = 9.8 Hz, 1H), 8.25 (d, J =7.9 Hz, 1H), 7.98-7.91 (m, 1H), 7.90-7.82 (m, 2H), 7.81 (d, J = 9.9 Hz,1H), 7.53 (d, J = 7.3 Hz, 2H), 7.45-7.39 (m, 2H), 7.38-7.33 (m, 1H),5.35 (s, 2H), 4.81 (s, 2H), 4.44-4.31 (m, 1H), 3.91 (quin, J = 8.5 Hz,1H), 2.85 (s, 6H), 2.68-2.62 (m, 1H), 2.44-2.33 (m, 3H), 2.29-a]pyridine-3- 2.17 (m, 2H), 2.05 (br t, J =10.1 Hz, 1H) carboxamide 131

6-((1,3- difluoropropan- 2-yl)oxy)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3] 494   E: 1.64 F: 1.65 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.26 (brt, J = 8.9 Hz, 2H), 8.11 (d, J = 9.8 Hz, 1H), 7.95-7.89 (m, 1H),7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.34 (dd, J = 9.8, 1.5 Hz, 1H),4.98 (br t, J = 20.9 Hz, 1H), 4.85 (br d, J = 9.8 Hz, 1H), 4.79-4.70 (m,2H), 4.65 (dd, J = 10.4, 5.2 Hz, 1H), 4.42-4.31 (m, heptan-2- 1H), 3.90(quin, J = 8.4 Hz, 1H), 2.67-2.58 (m, 1H), 2.45- yl)pyrazolo[1,5- 2.32(m, 3H), 2.29-2.15 (m, 2H), 2.04 (br t, J = 10.1 Hz, a]pyridine-3- 1H)carboxamide 132

6-((1,1- dioxidotetrahydro- 2H-thiopyran-4-yl) oxy)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3] 548.3 E: 1.47 F:1.48 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.69 (s, 1H), 8.47(s, 1H), 8.26 (t, J = 8.1 Hz, 2H), 8.11 (d, J = 9.8 Hz, 1H), 7.95-7.89(m, 1H), 7.88-7.85 (m, 1H), 7.85- 7.80 (m, 1H), 7.38 (br d, J = 9.5 Hz,1H), 4.72 (br t, J = 4.4 Hz, 1H), 4.42-4.30 (m, 1H), 3.95-3.84 (m, 1H),3.31- 3.20 (m, 2H), 3.1.9-3.09 (m, 2H), 2.67-2.60 (m, 1H), 2.44-2.31 (m,3H), 2.28-2.15 (m, 6H), 2.04 (br t, J = 10.1 heptan-2- Hz, 1H)yl)pyrazolo[1,5- yl)pyridine-3- carboxamide 133

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3,3,3- trifluoropropoxy) 512.3 E: 1.81 F: 1.81 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.28 (brd, J = 7.6 Hz, 1H), 8.25 (br d, J = 8.2 Hz, 1H), 8.09 (d, J = 9.8 Hz,1H), 7.94-7.89 (m, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.85-7.80 (m, 1H),7.24 (br d, J = 9.5 Hz, 1H), 4.40-4.32 (m, 1H), 4.28 (t, J = 5.8 Hz,2H), 3.90 (quin, J = 8.4 Hz, 1.11), 2.88-2.77 (m, 2H), 2.62pyrazolo[1,5-a] (br t, J = 11.7 Hz, 1H), 2.43-2.32 (m, 3H), 2.27-2.17(m, pyridine-3- 2H), 2.08-2.00 (m, 1H) carboxamide 134

6-((4.4- difluorocyclohexyl) oxy)- N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 534.1 E: 1.88 F: 1.92 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.25(br d, J = 7.3 Hz, 2H), 8.09 (br d, J = 9.8 Hz, 1H), 7.96-7.89 (m, 1H),7.89-7.85 (m, 1H), 7.85-7.80 (m, 1H), 7.31 (br d, J = 9.5 Hz, 1H), 4.62(br s, 1H), 4.42-4.29 (m, 1H), 3.90 (br t, J = 8.4 Hz, 1H), 2.67- 2.59(m, 1H), 2.44-2.31 (m, 3H), 2.29-2.16 (m, 2H), 2.13-1.99 (m, 4H),1.99-1.90 (m, 4H), 1.85 (br d, J = 6.4 2-yl)pyrazolo[1,5- Hz, 2H)a]pyridine-3- carboxamide 135

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-((tetrahydro- 2H-pyran- 500.1 E: 1.56 F: 1.62 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 8.25 (br d, J= 7.9 Hz, 2H), 8.08 (d, J = 9.8 Hz, 1H), 7.97-7.89 (m, 1H), 7.89-7.85(m, 1H), 7.85-7.80 (m, 1H), 7.28 (br d, J = 9.8 Hz, 1H), 4.65-4.56 (m,1H), 4.41-4.30 (m, 1H), 3.95-3.82 (m, 3H), 3.53- 3.44 (m, 1H), 2.66-2.57(m, 1H), 2.56 (br s, 1H), 2.43- 4-yl)oxy)pyrazolo 2.32 (m, 3H),2.27-2.16 (m, 2H), 2.08-1.95 (m, 3H), [1,5- 1.67-1.53 (m, 2H)a]pyridine-3- carboxamide 136

methyl 3-((3-(((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)carbamoyl) pyrazolo [1,5-a]pyridin-6- 529.1 E:1.54 F: 1.59 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.47 (s,1H), 8.32 (s, 1H), 8.26 (br t, J = 7.6 Hz, 2H), 8.11 (d, J = 9.8 Hz,1H), 7.97-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.30-7.23(m, 1H), 5.09 (br s, 1H), 4.40 (br d, J = 7.9 Hz, 2H), 4.38-4.31 (m,1H), 3.96-3.84 (m, 3H), 3.58 (s, 3H), 2.66-2.59 (m, 1H), 2.59-2.55 (m,1H), 2.45-2.32 (m, 3H), 2.29-2.16 (m, 2H), 2.04 (br t,yl)oxy)azetidine-1- J = 10.1 Hz, 1H) carboxylate 137

6-hydroxy-N-((aR)- 6-4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2- yl)pyrazolo[1,5- a]pyridine-3- 416.2 E: 1.22 F:1.24 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.39 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 8.21 (br d, J = 7.7 Hz, 1H), 8.14 (d, J = 1.3 Hz,1H), 8.04 (d, J = 9.5 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H),7.86-7.81 (m, 1H), 7.17 (dd, J = 9.6, 1.9 Hz, 1H), 4.40-4.32 (m, 1H),3.90 (quin, J = 8.4 Hz, 1H), 2.62 (br t, J = 11.6 Hz, 1H), 2.58-2.55 (m,1H), 2.44-2.32 (m, 3H), 2.26-2.16 (m, 2H), 2.03 (t, carboxamide J = 10.0Hz, 1H) 138

6-((3,3- difluorocyclo- butoxy)- N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1- yl)spiro[3.3] heptan-2- 506   E: 1.66 F: 1.69 ¹HNMR: (500 MHz, CD₃OD) δ ppm 12.49 (s, 1H), 8.47 (s, 1H), 8.40 (s, 1H),8.29 (br d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 9.6Hz, 1H), 7.94-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.26(dd, J = 9.6, 1.7 Hz, 1H), 4.83 (br s, 1H), 4.41-4.31 (m, 1H), 3.90(quin, J = 8.4 Hz, 1H), 3.32-3.1.9 (m, 1H), 2.81-2.69 (m, 2H), 2.66-2.59(m, 1H), 2.59-2.55 (m, 1H), 2.42- 2.30 (m, 3H), 2.26-2.16 (m, 2H), 2.03(br t, J = 10.0 Hz, yl)pyrazolo[1,5- 1H) a]pyridine-3- carboxamide 139

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)-6-(2-(2,2,2- trifluoroethoxy) ethoxy) 542.1 E: 1.76 F: 1.75 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.46 (br d, J = 9.8 Hz, 2H),8.29-8.23 (m, 2H), 8.08 (d, J = 9.5 Hz, 1H), 7.95-7.89 (m, 1H),7.89-7.86 (m, 1H), 7.86- 7.79 (m, 1H), 7.27 (br d, J = 9.5 Hz, 1H),4.42-4.32 (m, 1H), 4.21 (br s, 2H), 4.16 (q, J = 9.5 Hz, 2H), 3.96 (brs, 2H), 3.90 (br t, J = 8.5 Hz, 1H), 2.62 (br s, 1H), 2.44-2.31 (m, 3H),2.27-2.16 (m, 2H), 2.04 (br t, J = 9.9 Hz, 1H) pyrazolo[1,5-a] pyridine-3-carboxamide 140

6-((5-cyclopropyl- 1,3,4-thiadiazol-2-yl) methoxy)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- 554.1 E: 1.72 F: 1.76 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 8.30 (br d, J= 7.3 Hz, 1H), 8.24 (s, 1H), 8.10 (br d, J = 9.5 Hz, 1H), 7.96-7.89 (m,1H), 7.89- 7.78 (m, 2H), 7.32 (br d, J = 9.5 Hz, 1H), 5.58 (s, 2H),4.44- 4.28 (m, 1H), 3.90 (br t, J = 8.5 Hz, 1H), 2.62 (br s, 1H),2.45-2.31 (m, 3H), 2.27-2.14 (m, 2H), 2.09-1.97 (m, yl)spiro[3.3]heptan-1H), 1.22 (br d, J = 5.8 Hz, 2H), 1.03 (br s, 2H) 2-yl)pyrazolo[1,5-a]pyridine-3- carboxamide 141

6-(benzyloxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)-7- (trifluoromethyl) 574.3 E: 2.07 F: 2.04 ¹HNMR (500 MHz DMSO-d₆) δ ppm 12.50 (s, 1H), 8.57 (s, 1H), 8.51 (br d, J =7.4 Hz, 1H), 8.41 (br d, J = 9.8 Hz, 1H), 8.24 (br d, J = 7.7 Hz, 1H),7.95-7.88 (m, 1H), 7.86 (br d, J = 8.7 Hz, 1H), 7.84-7.75 (m, 1H),7.47-7.36 (m, 4H), 7.34 (br d, J = 7.1 Hz, 1H), 5.34 (s, 2H), 4.41-4.30(m, 1H), 3.94-3.84 (m, 1H), 2.62 (br s, 1H), 2.59-2.54 pyrazolo (m, 1H),2.42-2.29 (m, 4H), 2.28-2.15 (m, 2H), 2.03 (br [1,5-a]pyridine-3- t, J =9.9 Hz, 1H) carboxamide

Example 142:6-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl1)-1H-indazole-3-carboxamide

Intermediate 68 (15 mg, 0.027 mmol), cyclopropylboronic acid (9.36 mg,0.109 mmol), palladium(II) acetate (0.6 mg, 3 μmol),tricyclohexylphosphonium tetrafluoroborate (2.0 mg, 5.5 μmol) andphosphoric acid, potassium salt (17 mg, 0.082 mmol) were placed in apressure vial, and the mixture was degassed (3× Ar/vacuum). Then, PhMe(2.0 mL) and water (0.2 mL) were added, and the reaction mixture wasdegassed again. Afterwards, the vial was capped, the reaction mixturewas heated to 150° C. under microwave irradiation for 15 min. Solventwas removed under reduced pressure, the residue was diluted with DMF,filtered and purified by preparative HPLC to afford Example 142 (3.1 mg,22% yield) was obtained. MS(ESI) m/z: 512.3 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.38 (br d, J=8.0 Hz, 1H), 8.25 (d, J=7.8Hz, 1H), 8.11-8.02 (m, 1H), 7.99-7.78 (m, 5H), 7.43 (s, 1H), 6.95 (d,J=8.5 Hz, 1H), 4.47-4.34 (m, 2H), 4.32 (s, 2H), 3.95-3.84 (m, 1H),2.44-2.27 (m, 4H), 2.26-2.10 (m, 3H), 2.07-1.97 (m, 1H), 1.12 (s, 6H),1.04-0.94 (m, 2H), 0.75 (br d, J=4.9 Hz, 2H). HPLC RT=E: 1.84 F: 1.72.

Example 143:1-(2-hydroxy-2-methylpropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-phenyl-1H-indazole-3-carboxamide

Intermediate 68 (15 mg, 0.027 mmol), phenylboronic acid (10 mg, 0.082mmol) and Pd-XPhos G3 (1.7 mg, 2.0 μmol) were placed in a pressure vial.Then THF (1.25 mL) and phosphoric acid, potassium salt (0.5 M aq.)(0.109 mL, 0.055 mmol) were added, and the reaction mixture was degassed(3×, vacuum/Ar). The pressure vial was capped, and the reaction mixturewas stirred at 120° C., for 30 min. Most of the solvent was removedunder reduced pressure. Most of the solvent was removed under reducedpressure, the obtained residue was diluted with DMF (2 mL), filtered andpurified by preparative HPLC to give Example 143 (6.0 mg, 39% yield) wasobtained. MS(ESI) m/z; 548.40 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.47 (s, 1H), 8.42 (br d, J=7.9 Hz, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.19(d, J=8.5 Hz, 1H), 8.05 (s, 1H), 7.96-7.87 (m, 2H), 7.86-7.82 (m, 1H),7.86-7.82 (m, 1H), 7.77 (d, J=7.3 Hz, 2H), 7.58-7.54 (m, 1H), 7.56 (dd,J=8.4, 0.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.43-7.37 (m, 1-), 4.78-4.72(m, 1H), 4.74 (s, 1H), 4.45 (s, 2H), 4.45-4.39 (m, 1H), 2.67-2.56 (m,2H), 2.45-2.33 (m, 4H), 2.28-2.14 (m, 2H), 1.17 (s, 6H). HPLC RT=E: 1.98F: 1.97.

The following Examples in Table 8 were prepared by using a similarprocedure as shown in Example 143 by reacting Intermediate 68 with theappropriate boronic acids/boronate esters/potassium trifluoroborates.

HPLC Method, LCMS RT Ex. R Name (M + H)⁺ (min.) ¹H NMR 144

6-(4-chloro- phenyl)-1-(2- hydroxy-2- methylpropyl)- N-((aR)-6-(4-oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 582.4 E: 2.13 F: 2.12 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.44 (br d, J = 7.9 Hz, 1H), 8.27 (d, J =7.9 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.96-7.91 (m, 1H),7.96-7.91 (m, 1H), 7.91-7.87 (m, 1H), 7.87-7.83 (m, 1H), 7.81 (d, J =8.5 Hz, 2H), 7.62-7.50 (m, 2H), 4.76 (s, 1H), 4.50-4.41 (m, 3H), 3.96-3.91 (m, 1H), 2.67-2.56 (m, 2H), 2.47- 2.33 (m, 4H), 2.28-2.16 (m, 2H),1.18 (s, 6H) 145

1-(2-hydroxy-2- methylpropyl)- 6-(1-methyl- 1H-pyrazol-3-yl)-N-((aR)-6-(4- oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 552.5 E: 1.55 F: 1.58 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.46 (br d, J = 7.9 Hz, 1H), 8.26 (d, J =7.6 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.93-7.90 (m, 1H),7.90-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.42-7.30 (m, 1H), 6.47 (d, J = 1.8 Hz, 1H), 4.73 (s, 1H), 4.51-4.36 (m, 3H),3.98- 3.90 (m, 1H), 3.90 (s, 3H), 2.70-2.56 (m, 2H), 2.46-2.31 (m, 4H),2.29-2.14 (m, 2H), 1.16 (s, 6H) 146

1-(2-hydroxy-2- methylpropyl)- 6-(1-methyl- 1H-pyrazol-5-yl)-N-((aR)-6-(4- oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 552.4 E: 1.56 F: 1.59 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.46 (br d, J = 7.9 Hz, 1H), 8.26 (d, J =7.9 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.97-7.87 (m, 3H), 7.86- 7.81 (m,1H), 7.51 (d, J = 1.8 Hz, 1H), 7.40-7.34 (m, 1H), 6.47 (d, J = 1.5 Hz,1H), 4.48-4.40 (m, 3H), 3.96-3.91 (m, 1H), 3.90 (s, 3H), 2.66-2.56 (m,2H), 2.45-2.32 (m, 4H), 2.28-2.14 (m, 2H), 1.16 (s, 6H) 147

1-(2-hydroxy-2- methylpropyl)- 6-(1-methyl-1H- pyrazol-4-yl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 552.5 E: 1.53 F: 1.53 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.37 (br d, J = 7.9 Hz, 1H), 8.26 (d, J =7.9 Hz, 1H), 8.21 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H),7.94-7.86 (m, 3H), 7.86-7.81 (m, 1H), 7.46 (d, J = 9.2 Hz, 1H),4.47-4.39 (m, 1H), 4.38 (s, 2H), 3.94-3.90 (m, 1H), 3.89 (s, 3H),2.67-2.54 (m, 2H), 2.46-2.31 (m, 4H), 2.27-2.13 (m, 2H), 1.17 (s, 6H)148

1-(2-hydroxy-2- methylpropyl)- N-((aR)-6- (4-oxo-3,4- dihydro-phthalazin-1- yl)spiro[3.3] heptan-2-yl)- 6-((E)-styryl)- 1H-indazole-3-carboxamide 574.3 E: 2.09 F: 2.10 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm8.42 (br d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 8.5Hz, 1H), 7.96-7.90 (m, 2H), 7.89-7.81 (m, 2H), 7.63 (d, J = 7.6 Hz, 2H),7.57 (d, J = 8.5 Hz, 1H), 7.44-7.35 (m, 4H), 7.32-7.25 (m, 1H), 4.81 (s,1H), 4.47-4.40 (m, 1H), 4.39 (s, 2H), 2.67-2.55 (m, 2H), 2.44-2.29 (m,4H), 2.27-2.20 (m, 1H), 2.19-2.11 (m, 1H), 1.17 (s, 6H) 149

6-((E)-2- cyclopropyl- vinyl)-1-(2- hydroxy-2- methylpropyl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 538.3 E: 1.98 F: 1.99 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 8.37 (br s, 1H), 8.25 (br s, 1H), 7.98 (br d, J = 7.3 Hz,1H), 7.91 (br s, 1H), 7.89- 7.76 (m, 2H), 7.61 (br s, 1H), 7.29 (br d, J= 6.7 Hz, 1H), 6.57 (br d, J = 15.3 Hz, 1H), 6.02-5.91 (m, 1H), 4.76 (brs, 1H), 4.40 (br s, 1H), 4.33 (br s, 2H), 3.88 (br s, 1H), 2.58 (br d, J= 9.8 Hz, 2H), 2.44- 2.27 (m, 4H), 2.26-2.08 (m, 2H), 1.61 (br s, 1H),1.13 (br s, 6H), 0.82 (br s, 2H), 0.53 (br s, 2H) 150

1-(2-hydroxy-2- methylpropyl)- 6-(6-methoxy- pyridin-2-yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 579.3 E: 1.89 F: 1.94 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.47 (br d, J = 7.9 Hz, 1H), 8.42 (s, 1H),8.25 (t, J = 3.7 Hz, 2H), 8.18 (d, J = 8.5 Hz, 1H), 8.03-7.97 (m, 1H),7.95-7.90 (m, 1H), 7.89-7.77 (m, 3H), 7.67 (d, J = 7.6 Hz, 1H), 6.81 (d,J = 7.9 Hz, 1H), 4.51-4.36 (m, 3H), 3.98 (s, 3H), 3.95-3.85 (m, 1H),2.70-2.55 (m, 2H), 2.47-2.29 (m, 4H), 2.29-2.20 (m, 1H), 2.20-2.11 (m,1H), 1.17 (s, 6H) 151

6-((Z)-2- cyclopropyl- vinyl)-1-(2- hydroxy-2- methylpropyl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 538.3 E: 2.04 F: 2.05 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.47 (s, 1H), 8.42 (br d, J = 8.2 Hz, 1H), 8.25 (d, J =7.9 Hz, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.88-7.79 (m,3H), 7.15 (d, J = 8.5 Hz, 1H), 6.38 (br d, J = 15.9 Hz, 1H), 5.70-5.60(m, 1H), 4.46-4.38 (m, 2H), 3.95-3.89 (m, 1H), 2.66-2.58 (m, 2H),2.44-2.28 (m, 4H), 2.27-2.18 (m, 1H), 2.17-2.09 (m, 1H), 1.76 (d, J =6.1 Hz, 2H), 1.13 (s, 8H) 152

6-bromo-1- (2-hydroxy-2- methylpropyl)- N-((aR)-6- (4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)- 1H-indazole-3-carboxamide 550.3 E: 1.83 F: 1.80 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46(s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.26 (dd, J = 8.0, 0.8 Hz, 1H), 8.10(d, J = 1.1 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.98-7.85 (m, 2H),7.86-7.80 (m, 1H), 7.36 (dd, J = 8.7, 1.5 Hz, 1H), 4.70 (s, 1H), 4.37(s, 2H), 4.03 (q, J = 7.2 Hz, 1H), 3.90 (quin, J = 8.5 Hz, 1H),2.65-2.54 (m, 2H), 2.45-2.31 (m, 4H), 2.26-2.12 (m, 2H), 1.15 (s, 6H)153

1-(2-hydroxy-2- methylpropyl)- 6-(4-methoxy- phenyl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 578.4 E: 1.95 F: 1.96 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.44 (br d, J = 7.9 Hz, 1H), 8.25 (br d, J= 7.6 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.91 (br d, J =7.0 Hz, 1H), 7.89-7.80 (m, 2H), 7.70 (br d, J = 8.5 Hz, 2H), 7.51 (br d,J = 8.2 Hz, 1H), 7.05 (br d, J = 8.5 Hz, 2H), 4.43 (s, 2H), 4.41-4.37(m, 1H), 3.90 (br t, J = 8.5 Hz, 1H), 3.80 (s, 3H), 2.59 (br d, J = 10.1Hz, 2H), 2.44-2.29 (m, 5H), 2.23 (br d, J = 4.6 Hz, 1H), 2.19-2.11 (m,1H), 1.16 (s, 6H) 154

1-(2-hydroxy-2- methylpropyl)-6- (1-methyl-1H- 1,2,3-triazol-4-yl)-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)- 1H-indazole-3- carboxamide 553.3 E: 1.43 F: 1.43 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.56 (s, 1H), 8.44 (d, J = 7.9Hz, 1H), 8.29-8.22 (m, 2H), 8.16 (d, J = 8.2 Hz, 1H), 7.96-7.78 (m, 3H),7.70 (d, J = 8.2 Hz, 1H), 4.80 (s, 1H), 4.41 (s, 2H), 4.11 (s, 3H), 3.90(quin, J = 8.5 Hz, 1H), 2.68-2.55 (m, 3H), 2.45-2.29 (m, 4H), 2.27-2.11(m, 2H), 1.17 (s, 6H) 155

6-(3,5- dimethyl- isoxazol-4- yl)-1-(2-hydroxy- 2-methylpropyl)-N-((aR)-6-(4- oxo-3,4-dihydro- naphthalazin-1- yl)spiro[3.3]heptan-2-yl)- 1H-indazole-3- carboxamide 567.3 E: 1.72 F: 1.77 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.44 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.21(d, J = 7.6 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.92-7.85 (m, 1H),7.84-7.76 (m, 2H), 7.70 (s, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.82 (s, 1H),3.86 (quin, J = 8.4 Hz, 1H), 2.64-2.53 (m, 2H), 2.38 (s, 3H), 2.36-2.24(m, 4H), 2.21 (s, 4H), 2.15- 2.05 (m, 1H), 1.10 (s, 6H) 156

6-(3- chlorophenyl)-1- (2-hydroxy-2- methylpropyl)- N-((aR)-6-(4-oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 582.3 E: 2.10 F: 2.09 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.46 (br d, J = 7.9 Hz, 1H), 8.25 (br d, J= 7.9 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H), 7.98- 7.79 (m,4H), 7.74 (br d, J = 7.6 Hz, 1H), 7.60-7.50 (m, 2H), 7.46 (br d, J = 7.3Hz, 1H), 4.80 (s, 1H), 4.46 (s, 2H), 4.45-4.37 (m, 1H), 3.90 (quin, J =8.5 Hz, 1H), 2.69-2.55 (m, 2H), 2.46-2.30 (m, 4H), 2.29-2.11 (m, 2H),1.16 (s, 6H) 157

1-(2-hydroxy-2- methylpropyl)- 6-(2-methoxy- phenyl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 578.3 E: 1.92 F: 1.92 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.42 (br d, J = 8.2 Hz, 1H), 8.25 (br d, J= 7.6 Hz, 1H), 8.10 (br d, J = 8.5 Hz, 1H), 7.98-7.79 (m, 4H), 7.41-7.31(m, 3H), 7.13 (br d, J = 8.2 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H),4.49-4.41 (m, 1H), 4.39 (s, 2H), 3.90 (quin, J = 8.4 Hz, 1H), 3.76 (s,3H), 2.68-2.55 (m, 2H), 2.46-2.28 (m, 4H), 2.28-2.20 (m, 1H), 2.20-2.12(m, 1H), 1.15 (s, 6H) 158

1-(2-hydroxy-2- methylpropyl)- 6-(3-methoxy- phenyl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 578.3 E: 1.93 F: 1.93 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 8.45 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.17(d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.96-7.90 (m, 1H), 7.90-7.80 (m, 2H),7.55 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.44-7.35 (m, 1H),7.33 (br d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.00-6.93 (m, 1H), 4.45 (s,2H), 4.44- 4.36 (m, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 3.84 (s, 3H),2.67-2.56 (m, 2H), 2.45-2.30 (m, 4H), 2.28-2.20 (m, 1H), 2.20-2.13 (m,1H), 1.16 (s, 6H) 159

6-(2,6- difluorophenyl)- 1-(2-hydroxy-2- methylpropyl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 584.2 E: 1.96 F: 2.06 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.44 (s, 1H), 8.49 (br d, J = 7.9 Hz, 1H), 8.21 (br d, J= 7.6 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.92-7.86 (m, 1H), 7.85- 7.75(m, 3H), 7.50-7.39 (m, 1H), 7.27- 7.15 (m, 3H), 4.42-4.37 (m, 1H), 4.36(s, 2H), 3.91-3.80 (m, 1H), 2.66-2.55 (m, 1H), 2.41-2.55 (m, 4H), 2.19(br d, J = 4.9 Hz, 1H), 2.15-2.07 (m, 1H), 1.09 (s, 6H) 160

6-(2-cyanophenyl)- 1-(2-hydroxy- 2-methylpropyl)- N-((aR)-6-(4-oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3] heptan-2-yl)-1H-indazole-3- carboxamide 573.3 E: 1.78 F: 1.78 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.52 (br d, J = 7.9 Hz, 1H), 8.29-8.21 (m,2H), 8.02-7.96 (m, 2H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.79(m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.43 (d, J= 8.2 Hz, 1H), 4.77 (s, 1H), 4.49-4.39 (m, 3H), 3.91 (quin, J = 8.3 Hz,1H), 2.68-2.56 (m, 2H), 2.38 (td, J = 20.1, 9.9 Hz, 4H), 2.29-2.21 (m,1H), 2.21-2.13 (m, 1H), 1.16 (s, 6H) 161

1-(2-hydroxy-2- methylpropyl)- 6-(isoxazol- 4-yl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)- 1H-indazole-3-carboxamide 539.4 E: 1.48 F: 1.25 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47(s, 1H), 8.40 (br dd, J = 28.5, 8.1 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H),8.09- 7.97 (m, 2H), 7.94-7.80 (m, 3H), 7.55- 7.25 (m, 1H), 4.46-4.23 (m,3H), 3.90 (quin, J = 8.5 Hz, 1H), 2.66-2.55 (m, 2H), 2.45-2.27 (m, 5H),2.24-2.08 (m, 2H), 1.13 (br s, 6H)

The following Examples in Table 9 were made by using the same procedureas shown in Example 1. Intermediate 69 was coupled with the appropriateacid. Various coupling reagents could be used other than the onedescribed in Example 1 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 9 HPLC Method, LCMS RT Ex. R Name (M + H)⁺ (min.) ¹H NMR 162

N-(6-fluoro-6- (4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1- (2-hydroxy-2- methylpropyl)-1H- indazole-3- carboxamide490.1 E: 1.55 F: 1.55 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.82 (br s, 1H),8.43 (br d, J = 7.8 Hz, 1H), 8.31 (br d, J = 7.7 Hz, 1H), 8.11 (br d, J= 8.1 Hz, 1H), 8.02-7.84 (m, 3H), 7.76 (br d, J = 8.4 Hz, 1H), 7.40 (brt, J = 7.5 Hz, 1H), 7.22 (br t, J = 7.4 Hz, 1H), 4.48-4.38 (m, 1H), 4.36(s, 2H), 3.11 (br t, J = 13.4 Hz, 1H), 3.03-2.91 (m, 1H), 2.86-2.74 (m,1H), 2.45-2.35 (m, 1H), 2.26-2.09 (m, 2H), 1.13 (s, 6H) 163

6-fluoro-N- (6-fluoro-6-(4- oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)- 1-(2-hydroxy-2- methylpropyl)-1H- indazole-3- carboxamide508.1 E: 1.62 F: 1.63 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.82 (s, 1H),8.49 (br d, J = 7.8 Hz, 1H), 8.31 (br d, J = 7.7 Hz, 1H), 8.10 (br dd, J= 8.6, 5.4 Hz, 1H), 8.00-7.93 (m, 1H), 7.93-7.84 (m, 2H), 7.61 (br d, J= 9.6 Hz, 1H), 7.11 (br t, J = 8.3 Hz, 1H), 4.44- 4.35 (m, 1H), 4.32 (s,2H), 3.10 (br t, J = 12.4 Hz, 1H), 2.95 (br t, J = 12.1 Hz, 1H), 2.81(br dd, J = 21.7, 12.6 Hz, 1H), 2.69 (br d, J = 13.7 Hz, 1H), 2.44-2.34(m, 1H), 2.25-2.09 (m, 2H), 1.13 (s, 6H) 164

N-(6-fluoro-6- (4-oxo-3,4-dihydro- phthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo [1,5-a]pyridine- 3-carboxamide 418.1 E: 1.32 F: 1.31 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.82 (s, 1H), 8.74 (br d, J = 6.7 Hz,1H), 8.53 (s, 1H), 8.36-8.25 (m, 2H), 8.16 (br d, J = 8.8 Hz, 1H),8.00-7.94 (m, 1H), 7.94-7.84 (m, 2H), 7.43 (br t, J = 7.8 Hz, 1H), 7.04(br t, J = 6.6 Hz, 1H), 4.42-4.28 (m, 1H), 3.14-3.05 (m, 1H), 2.97 (brt, J = 12.4 Hz, 1H), 2.87-2.68 (m, 2H), 2.33-2.16 (m, 2H), 2.03 (br t, J= 9.9 Hz, 1H)

Example 165:N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Pyrrolidin-2-one (0.012 mL, 0.16 mmol), copper(I) iodide (3.0 mg, 0.016mmol) and N1,N2-dimethylethane-1,2-diamine (1.7 μl, 0.016 mmol) wereplaced in a pressure vial, and dioxane (0.75 mL) was added, followed byIntermediate 70 (15 mg, 0.031 mmol) and Phosphoric acid, potassium salt(17 mg, 0.078 mmol). The reaction mixture was degassed (3×, vacuum/Ar),the pressure vial was capped, and the reaction mixture was stirred at105° C., for 16 h. Most of the solvent was removed under reducedpressure, the residue was diluted with DMF (2 mL), acidified with TFA,filtered and purified by preparative HPLC to afford Example 165 (1.3 mg,9% yield). MS(ESI) m/z: 483.35 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 5 ppm12.47 (s, 1H), 9.07 (s, 1H), 8.53 (s, 1H), 8.32 (br d, J=7.6 Hz, 1H),8.25 (br d, J=7.6 Hz, 1H), 8.16 (br d, J=9.5 Hz, 1H), 7.95-7.90 (m, 1H),7.88-7.80 (m, 3H), 4.42-4.30 (m, 1H), 3.94-3.83 (m, 3H), 2.63 (br s,2H), 2.45-2.31 (m, 4H), 2.28-2.17 (m, 3H), 2.12-2.00 (m, 3H). HPLC RT=E:1.31F; 1.32.

The following Examples in Table 10 were prepared by using similarprocedures as outlined in Example 142, Example 143. Intermediate 54A andExample 165 by reacting Intermediate 70 with the appropriate boronicacids/boronate esters/potassium trifluoroborates, inorganic cyanides,amides, alcohols and heterocycles.

TABLE 10 HPLC Meth- LCMS od, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 166

6-cyclopropyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a] pyridine-3- carboxamide 440.2E: 1.52 F: 1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.56 (s,1H), 8.47 (s, 1H), 8.26 (br dd, J = 13.0, 7.8 Hz, 2H), 8.06 (br d, J =8.9 Hz, 1H), 7.96-7.89 (m, 1H), 7.89-7.78 (m, 2H), 7.17 (br d, J = 9.2Hz, 1H), 4.42-4.30 (m, 1H), 3.90 (br t, J = 8.4 Hz, 1H), 2.62 (br s,1H), 2.44-2.30 (m, 3H), 2.27-2.15 (m, 2H), 2.08-1.95 (m, 2H), 0.95 (brd, J = 7.3 Hz, 2H), 0.76 (br d, J = 4.1 Hz, 2H) 167

6-(1-(difluoromethyl)- 1H-pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3- carboxamide 516.1 E: 1.45 F: 1.46 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.49 (s, 1H), 9.22 (s, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 8.43 (s,1H), 8.37 (br d, J = 7.6 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.20 (d,J = 9.2 Hz, 1H), 7.95-7.76 (m, 5H), 4.45-4.31 (m, 1H), 3.96- 3.85 (m,1H), 2.64 (br s, 1H), 2.57 (br t, J = 8.0 Hz, 1H), 2.44-2.31 (m, 3H),2.29-2.17 (m, 2H), 2.05 (br t, J = 10.0 Hz, 1H) 168

6-cyano-N-((aR)-6- (4-oxo-3,4-dihydro- phthalazin-1-yl)spiro[3.3]heptan-2-yl) pyrazolo[1,5-a] pyridine- 3-carboxamide 426.2 E:1.39 F: 1.40 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.61 (s,1H), 8.75 (s, 1H), 8.52 (br d, J = 7.3 Hz, 1H), 8.25 (br d, J = 8.9 Hz,2H), 7.96-7.88 (m, 1H), 7.88-7.79 (m, 2H), 7.65 (d, J = 9.5 Hz, 1H),4.41-4.28 (m, 1H), 3.90 (quin, J = 8.5 Hz, 1H), 2.68-2.59 (m, 1H),2.45-2.30 (m, 3H), 2.27-2.16 (m, 2H), 2.04 (br t, J = 10.1 Hz, 1H) 169

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(2-oxopyridin- 1(2H)-yl)pyrazolo [1,5-a]pyridine- 3-carboxamide493.4 E: 1.25 F: 1.26 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H),9.09 (s, 1H), 8.65 (s, 1H), 8.41 (br d, J = 7.3 Hz, 1H), 8.24 (br t, J =9.0 Hz, 2H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86- 7.80 (m, 1H),7.78 (br d, J = 6.1 Hz, 1H), 7.56 (br t, J = 7.3 Hz, 1H), 7.51 (br d, J= 9.5 Hz, 1H), 6.53 (br d, J = 9.2 Hz, 1H), 6.37 (br t, J = 6.6 Hz, 1H),4.44-4.34 (m, 1H), 3.91 (br t, J = 8.4 Hz, 1H), 2.65 (br s, 1H),2.45-2.34 (m, 4H), 2.30-2.19 (m, 2H), 2.10-2.01 (m, 1H) 170

6-(1-methyl-1H- pyrazol-4-yl)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3- carboxamide 480.2 E: 1.27 F: 1.27 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.50 (s, 1H), 9.00 (s, 1H), 8.51 (s, 1H), 8.36 (br d, J = 7.3 Hz,1H), 8.28-8.21 (m, 2H), 8.15 (br d, J = 9.2 Hz, 1H), 7.99 (s, 1H),7.95-7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.70 (br d, J = 9.3 Hz, 1H),4.41-4.29 (m, 1H), 3.95-3.88 (m, 1H), 3.86 (s, 3H), 2.68-2.55 (m, 2H),2.44-2.30 (m, 3H), 2.27-2.15 (m, 2H), 2.04 (br t, J = 10.0 Hz, 1H) 171

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1-((S)- 3,3,3-trifluoro-2- hydroxypropyl)-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3- carboxamide 578.2 E: 1.40 F:1.41 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 9.05 (s, 1H), 8.52 (s, 1H),8.39-8.31 (m, 2H), 8.25 (br d, J = 7.8 Hz, 1H), 8.17 (br d, J = 9.2 Hz,1H), 8.11 (s, 1H), 7.96-7.89 (m, 1H), 7.89- 7.79 (m, 2H), 7.72 (br d, J= 9.1 Hz, 1H), 4.40- 4.31 (m, 1H), 4.29-4.19 (m, 1H), 3.96-3.84 (m, 1H),3.54 (br s, 2H), 2.63 (br s, 1H), 2.44- 2.30 (m, 3H), 2.29-2.17 (m, 2H),2.04 (br t, J = 10.0 Hz, 1H) 172

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3- (trifluoromethl)-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carboxamide 534.2 E: 1.44 F: 1.44 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50(s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.41 (br d, J = 7.5 Hz, 1H), 8.32(s, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.21 (br d, J = 9.2 Hz, 1H), 7.95-7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.49 (br d, J = 9.1 Hz, 1H), 4.43-4.31(m, 1H), 3.96-3.84 (m, 1H), 2.63 (br s, 1H), 2.60-2.55 (m, 1H),2.43-2.30 (m, 3H), 2.29-2.16 (m, 2H), 2.04 (br t, J = 10.0 Hz, 1H) 173

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(thiazol-2- yl)pyrazolo[1,5-a] pyridine-3- carboxamide 483.1 E:1.44 F: 1.44 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 9.30 (s, 1H), 8.65 (s,1H), 8.46 (br d, J = 7.4 Hz, 1H), 8.26 (br dd, J = 11.9, 8.9 Hz, 2H),8.03- 7.95 (m, 2H), 7.95-7.89 (m, 1H), 7.88-7.77 (m, 3H), 4.43-4.32 (m,1H), 3.96-3.85 (m, 1H), 2.64 (br s, 1H), 2.60-2.54 (m, 1H), 2.45- 2.30(m, 3H), 2.30-2.17 (m, 2H), 2.05 (br t, J = 10.1 Hz, 1H) 174

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1H-pyrazol-4- yl)pyrazolo[1,5-a] pyridine-3- carboxamide 466.2 E:1.16 F: 1.17 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 9.04 (s,1H), 8.50 (s, 1H), 8.37 (br d, J = 7.5 Hz, 1H), 8.24 (br d, J = 7.8 Hz,1H), 8.15 (br d, J = 9.2 Hz, 1H), 7.96-7.89 (m, 1H), 7.89-7.81 (m, 2H),7.76 (br d, J = 9.3 Hz, 1H), 4.41-4.29 (m, 1H), 3.90 (br t, J = 8.4 Hz,1H), 3.69 (br s, 1H), 2.62 (br s, 1H), 2.42-2.29 (m, 3H), 2.27-2.14 (m,2H), 2.04 (br t, J = 9.9 Hz, 1H) 175

6-(1,4-dimethyl-1H- 1,2,3-triazol-5-yl)- N-((aR)-6-(4- oxo-3,4-dihydro-phthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5a]- pyridine-3-carboxamide 495.2 E: 1.21 F: 1.22 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50(s, 1H), 9.09 (s, 1H), 8.68 (s, 1H), 8.43 (br d, J = 7.7 Hz, 1H), 8.30(br d, J = 9.1 Hz, 1H), 8.27 (br d, J = 7.9 Hz, 1H), 7.99-7.88 (m, 3H),7.86 (br d, J = 7.8 Hz, 1H), 7.56 (br d, J = 9.2 Hz, 1H), 4.41 (br d, J= 8.4 Hz, 1H), 3.99 (s, 3H), 3.93 (br t, J = 8.5 Hz, 1H), 2.67 (br d, J= 18.9 Hz, 1H), 2.41 (br dd, J = 13.9, 9.2 Hz, 3H), 2.32-2.18 (m, 5H),2.11-2.03 (m, 1H) 176

6-(1H-imidazol-1-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a] pyridine-3- carboxamide 466.1E: 1.09 F: 1.26 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.44 (s,1H), 9.00 (br s, 1H), 8.71 (s, 1H), 8.47 (br d, J = 7.3 Hz, 1H), 8.35(d, J = 9.5 Hz, 1H), 8.28 (br d, J = 7.9 Hz, 1H), 7.97- 7.92 (m, 1H),7.91-7.83 (m, 3H), 4.46-4.36 (m, 1H), 3.94 (br t, J = 8.5 Hz, 1H), 2.66(br s, 2H), 2.47-2.36 (m, 4H), 2.32-2.21 (m, 2H), 2.09 (br t, J = 10.1Hz, 1H) 177

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3] heptan-2-yl)-6-(1H-pyrazol-1- yl)pyrazolo[1,5-a] pyridine-3- 466.1 E: 1.39 F: 1.31 ¹HNMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.30 (s, 1H), 8.61 (br d, J= 6.1 Hz, 2H), 8.40 (br d, J = 7.4 Hz, 1H), 8.29 (br d, J = 9.5 Hz, 1H),8.25 (br d, J = 8.0 Hz, 1H), 8.06 (br d, J = 9.5 Hz, 1H), 7.97-7.76 (m,4H), 6.61 (br s, 1H), 4.46-4.33 (m, 1H), 3.97-3.83 (m, 1H), 2.64 (br s,1H), 2.58 (br s, carboxamide 1H), 2.45-2.31 (m, 3H), 2.30-2.17 (m, 2H),2.06 (br t, J = 9.9 Hz, 1H) 178

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1H-1,2,4- triazol-1-yl)pyrazolo [1,5-a]pyridine-3- carboxamide467.1 E: 1.20 F: 1.12 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),9.41 (s, 1H), 9.33 (s, 1H), 8.66 (s, 1H), 8.45 (br d, J = 7.5 Hz, 1H),8.39-8.30 (m, 2H), 8.25 (br d, J = 7.7 Hz, 1H), 7.97 (br d, J = 9.6 Hz,1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.81 (m, 1H), 4.43-4.35(m, 1H), 3.96- 3.87 (m, 1H), 2.64 (br s, 1H), 2.61-2.55 (m, 1H),2.45-2.31 (m, 3H), 2.29-2.19 (m, 2H), 2.06 (br t, J = 10.0 Hz, 1H) 179

6-(2-methoxy- ethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a] 474.1 E: 1.29 F: 1.26 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.45 (br d, J = 6.1 Hz, 2H),8.26 (t, J = 7.3 Hz, 2H), 8.07 (d, J = 9.6 Hz, 1H), 7.94-7.82 (m, 3H),7.26 (br d, J = 9.6 Hz, 1H), 4.40-4.32 (m, 1H), 4.15 (br d, J = 4.1 Hz,2H), 3.90 (br t, J = 8.5 Hz, 1H), 3.68 (br s, 2H), 2.62 (br s, 1H),pyridine-3- 2.54 (s, 3H), 2.44-2.31 (m, 3H), 2.26-2.17 (m, carboxamide2H), 2.04 (br t, J = 10.0 Hz, 1H) 180

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(4-oxopyridin- 1(4H)-yl)pyrazolo [1,5-a]pyridine-3- carboxamide493.2 E: 1.14 F: 1.20 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),9.30 (s, 1H), 8.70 (s, 1H), 8.44 (br d, J = 7.3 Hz, 1H), 8.30 (br d, J =9.5 Hz, 1H), 8.28 (br d, J = 7.6 Hz, 1H), 8.09 (br d, J = 7.0 Hz, 2H),7.93 (br d, J = 7.3 Hz, 1H), 7.92-7.88 (m, 1H), 7.88-7.82 (m, 1H), 7.73(br d, J = 9.8 Hz, 1H), 6.33 (br d, J = 7.3 Hz, 2H), 4.46-4.36 (m, 1H),3.98-3.88 (m, 1H), 2.65 (br s, 1H), 2.59 (br d, J = 10.4 Hz, 1H),2.48-2.35 (m, 3H), 2.32-2.20 (m, 2H), 2.12-2.03 (m, 1H)

Example 181: 6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 71 was purified by preparative HPLC to give rise to Example181. MS(ESI) m/z: 460.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.50(s, 1H), 8.43 (br d, J=10.4 Hz, 2H), 8.33 (br d, J=7.3 Hz, 1H), 8.27 (brd, J=7.9 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 7.99-7.91 (m, 1H), 7.90-7.81(m, 2H), 7.32-7.24 (m, 1H), 4.42-4.30 (m, 1H), 4.10-4.03 (m, 2H), 3.90(br dd, J=16.8, 8.2 Hz, 1H), 2.62 (br d, J=11.6 Hz, 2H), 2.44-2.31 (m,4H), 2.27-2.16 (m, 2H), 2.09-2.00 (m, 1H). HPLC RT=E: 1.23 F: 1.28.

Example 182:6-(2-(3-fluoroazetidin-1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

To a solution of Intermediate 72 (10 mg, 0.018 mmol) in DMF (1 mL) wassequentially added 3-fluoroazetidine, HCl (9.8 mg, 0.088 mmol), sodiumiodide (13.2 mg, 0.088 mmol) and K₂CO₃ (18.2 mg, 0.132 mmol). Thereaction vial was capped, and was stirred at 100° C., for 2 h. Thereaction mixture was cooled to rt, acidified with TFA, filtered, andpurified by preparative HPLC to give rise to Example 182 (0.8 mg, 6%yield) was obtained. MS(ESI) m/z: 517.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.50 (s, 1H), 8.44 (br d, J=7.7 Hz, 2H), 8.29 (br d,J=7.4 Hz, 1H), 8.26 (br d, J=7.9 Hz, 1H), 8.07 (br d, J=9.6 Hz, 1H),7.96-7.91 (m, 1H), 7.90-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.24 (br d,J=9.6 Hz, 1H), 5.15 (br d, J=58.1 Hz, 1H), 4.43-4.28 (m, 2H), 4.02 (brt, J=5.0 Hz, 2H), 3.98-3.84 (m, 1H), 3.71-3.58 (m, 1H), 2.92-2.79 (m,2H), 2.61 (br d, J=18.8 Hz, 2H), 2.44-2.31 (m, 3H), 2.27-2.15 (m, 3H),2.04 (br t, J=9.9 Hz, 1H). HPLC RT=E: 1.02 F: 1.33.

The following Examples in Table 11 were prepared by using a similarprocedure as shown in Example 182 by reacting Intermediate 72 with theappropriate amine or alcohol.

TABLE 11 HPLC Meth- LCMS od, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 183

6-(2-(dimethylamino) ethoxy)-N-((aR)-6- (4-oxo-3,4-dihydro-phthalazin-1-yl)spiro [3.3]heptan-2-yl)pyrazolo [1,5-a]pyridine-3- 487.4E: 0.99 F: 1.06 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.46 (brd, J = 10.5 Hz, 2H), 8.28 (br d, J = 7.7 Hz, 1H), 8.25 (br d, J = 7.8Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.96- 7.90 (m, 1H), 7.89-7.86 (m,1H), 7.86-7.80 (m, 1H), 7.24 (br d, J = 9.7 Hz, 1H), 4.41- carboxamide4.31 (m, 1H), 4.11 (br t, J = 5.4 Hz, 2H), 3.90 (quin, J = 8.5 Hz, 1H),2.69 (br t, J = 5.3 Hz, 2H), 2.65-2.57 (m, 2H), 2.44-2.32 (m, 3H), 2.25(s, 7H), 2.03 (br t, J = 10.0 Hz, 1H) 184

6-(2-(4-hydroxy-3,3- dimethylpiperidin-1- yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 571.1 E: 1.07 F: 1.30 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.28(br d, J = 7.6 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.06 (br d, J = 9.5Hz, 1H), 7.96-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.24(br d, J = 9.2 Hz, 1H), 4.40-4.31 (m, 1H), 4.10 (br s, 2H), 3.90 (br t,J = 8.4 Hz, 1H), 3.05 (br s, 1H), 2.78 (br s, 1H), 2.63 (br s, 3H),2.46-2.31 (m, 4H), 2.27-2.16 (m, 2H), 2.10-1.99 (m, 2H), 1.81 (br d, J =10.8 Hz, 1H), 1.54 (br s, 1H), 1.47 (br d, J = 9.3 Hz, 1H), 0.84 (br d,J = 3.8 Hz, 6H) 185

6-(2-(3,3- difluoropyrrolidin-1- yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 547.2 E: 1.28 F: 1.70 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.50 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.32 (br d, J= 7.6 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.10 (br d, J = 9.5 Hz, 1H),7.91 (br d, J = 7.4 Hz, 1H), 7.87 (br d, J = 7.8 Hz, 1H), 7.86-7.80 (m,3-carboxamide 1H), 7.31 (br d, J = 9.6 Hz, 1H), 4.40- 4.32 (m, 1H), 4.28(br s, 2H), 3.95-3.84 (m, 1H), 3.46 (br s, 2H), 2.62 (br s, 1H),2.59-2.55 (m, 1H), 2.43-2.29 (m, 4H), 2.27-2.15 (m, 2H), 2.03 (br t, J =10.1 Hz, 1H) 186

6-(2-(azetidin-1-yl)ethoxy)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 499.2E: 1.02 F: 1.04 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.56 (s,1H), 8.49 (s, 1H), 8.30 (br d, J = 7.7 Hz, 1H), 8.25 (br d, J = 8.0 Hz,1H), 8.12 (br d, J = 9.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H),7.86-7.82 (m, 1H), 7.28 (br d, J = 9.7 Hz, 1H), 4.43-4.32 (m, 1H), 4.26(br s, 2H), 4.15 (br d, J = 6.5 Hz, 4H), 3.91 (br t, J = 8.4 Hz, 1H),3.62 (br s, 1H), 2.99 (br s, 1H), 2.62 (br s, 1H), 2.45-2.32 (m, 4H),2.31-2.15 (m, 3H), 2.08-2.00 (m, 1H) 187

6-(2-(2,2-dimethyl- morpholino)ethoxy)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-557.2 E: 1.10 F: 1.55 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.45 (s, 1H),8.44 (s, 1H), 8.40 (s, 1H), 8.24 (br d, J = 7.3 Hz, 1H), 8.21 (br d, J =7.8 Hz, 1H), 8.02 (br d, J = 9.6 Hz, 1H), 7.92-7.86 (m, 1H), 7.85-7.82(m, 1H), 7.82-7.75 (m, 1H), 7.21 (br d, J = 3-carboxamide 9.5 Hz, 1H),4.38-4.27 (m, 1H), 4.14-4.05 (m, 2H), 3.92-3.80 (m, 1H), 3.54 (br s,1H), 2.62 (br t, J = 5.3 Hz, 2H), 2.58 (br s, 1H), 2.40-2.26 (m, 5H),2.24-2.10 (m, 4H), 1.99 (br t, J = 10.0 Hz, 1H), 1.09 (s, 6H) 188

6-(2-(4-methylpiperazin-1- yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 542.2 E: 0.94 F: 0.95 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.51 (s, 1H), 8.44 (br s, 2H), 8.32 (br d, J =7.5 Hz, 1H), 8.26 (br d, J = 7.6 Hz, 1H), 8.06 (br d, J = 9.6 Hz, 1H),7.92 (br d, J = 7.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.25 (br d, J = 8.1 Hz,1H), 4.41-4.28 (m, 1H), 4.12 (br s, 2H), 3.96-3.84 (m, 1H), 2.70 (br s,2H), 2.62 (br s, 1H), 2.44-2.32 (m, 6H), 2.28-2.17 (m, 3H), 2.14 (s,3H), 2.03 (br t, J = 9.9 Hz, 1H) 189

6-(2-((R)-3- fluoropyrrolidin-1- yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 531.2 E: 1.24 F: 1.24 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.44 (br d, J = 6.7 Hz, 2H), 8.30 (br d, J= 7.5 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.06 (br d, J = 9.6 Hz, 1H),7.95-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.26 (br d, J = 10.0 Hz, 1H), 5.193-carboxamide (br d, J = 55.8 Hz, 1H), 4.41-4.29 (m, 1H), 4.12 (br s,2H), 3.93-3.84 (m, 1H), 2.87 (br d, J = 15.0 Hz, 3H), 2.72 (br s, 1H),2.59 (br d, J = 27.4 Hz, 2H), 2.44- 2.30 (m, 4H), 2.25-2.17 (m, 2H),2.16- 2.06 (m, 1H), 2.03 (br t, J = 10.0 Hz, 1H), 1.84 (br s, 1H) 190

6-(2-((S)-3-fluoropyrrolidin- 1-yl)ethoxy)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 531.2 E: 1.36 F: 1.36 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.45 (br d, J = 9.3 Hz, 2H),8.31 (br d, J = 7.3 Hz, 1H), 8.25 (br d, J = 7.7 Hz, 1H), 8.07 (br d, J= 9.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.89- 7.86 (m, 1H), 7.85-7.80 (m, 1H),7.26 (br d, J = 9.6 Hz, 1H), 5.21 (br d, J = 56.3 Hz, 1H), 4.41-4.31 (m,1H), 4.14 (br s, 2H), 3.95-3.84 (m, 1H), 3.56 (br s, 1H), 2.91 (br s,2H), 2.59 (br d, J = 27.3 Hz, 2H), 2.43-2.30 (m, 3H), 2.26-2.17 (m, 2H),2.09 (br s, 1H), 2.03 (br t, J = 10.1 Hz, 1H), 1.96-1.80 (m, 1H

Example 191:6-(3-morpholinopropyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

To a solution of Intermediate 73 (10 mg, 0.022 mmol), morpholine (3.8μl, 0.044 mmol) and acetic acid (1.3 μl, 0.022 mmol) in anhydrous THF (1mL) was added sodium triacetoxyborohydride (14 mg, 0.066 mmol), and thereaction mixture was stirred at rt for 4 h. The reaction mixture wasquenched with TFA (CAUTION), solvent was removed under reduced pressure,the residue was suspended in DMF (2 mL), filtered, and purified bypreparative HPLC to afford Example 191 (9.3 mg, 80% yield). MS(ESI) m/z:527.0 (M+H)⁺, ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 8.61 (s,1H), 8.48 (s, 1H), 8.25 (br d, J=7.3 Hz, 1H), 8.22 (br d, J=7.9 Hz, 1H),8.10 (d, J=9.2 Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.76 (m, 2H), 7.34 (brd, J=9.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.90 (br s, 2H), 3.89-3.81 (m, 2H),3.75-3.70 (m, 1H), 3.63 (br s, 2H), 3.06 (br s, 2H), 2.66 (br t. J=7.3Hz, 2H), 2.62-2.55 (m, 1H), 2.40-2.28 (m, 3H), 2.24-2.13 (m, 2H),2.04-1.92 (m, 3H). HPLC RT=E: 1.21 F: 1.42.

The following Examples in Table 12 were prepared by using a similarprocedure as shown in Example 191 by reacting Intermediate 73 with theappropriate amine.

TABLE 12 HPLC Ex. R Name LCMS (M + H)⁺ Method, RT (min.) ¹H NMR 192

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3-(pyrrolidin-1- yl)propyl)pyrazolo[1,5- a]pyridine-3-carboxamide 511 E: 1.24 F: 1.25 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47(s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.25 (br d, J = 7.6 Hz, 2H), 8.10(d, J = 9.2 Hz, 1H), 7.95-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.79 (m,1H), 7.37 (br d, J = 9.5 Hz, 1H), 4.43-4.31 (m, 1H), 3.91 (br t, J = 8.4Hz, 1H), 2.71-2.60 (m, 3H), 2.43 (br d, J = 7.3 Hz, 4H), 2.41-2.33 (m,3H), 2.27-2.16 (m, 2H), 2.09-1.99 (m, 1H), 1.90 (s, 3H), 1.78 (br dd, J= 14.5, 7.5 Hz, 2H), 1.68 (br s, 4H) 193

6-(3-(dimethylamino)propyl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3- carboxamide 485.3E: 1.09 F: 1.01 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.61 (s,1H), 8.50 (s, 1H), 8.28 (br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.9 Hz,1H), 8.12 (br d, J = 8.9 Hz, 1H), 7.94-7.90 (m, 1H), 7.90-7.86 (m, 1H),7.86-7.81 (m, 1H), 7.38 (br d, J = 8.9 Hz, 1H), 4.42-4.32 (m, 1H), 3.91(br t, J = 8.3 Hz, 1H), 3.38 (br s, 2H), 2.68-2.60 (m, 3H), 2.44-2.32(m, 8H), 2.28- 2.18 (m, 2H), 2.04 (br t, J = 10.0 Hz, 1H), 1.88-1.79 (m,2H) 194

6-(3-(cyclopropylamino)propyl)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 497 E: 1.08 F: 1.09 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.51 (s, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 8.32 (br s, 1H), 8.26(br d, J = 7.7 Hz, 1H), 8.13 (br d, J = 8.9 Hz, 1H), 7.97-7.91 (m, 1H),7.90- 7.87 (m, 1H), 7.87-7.80 (m, 1H), 7.38 (br d, J = 9.2 Hz, 1H),4.43-4.33 (m, 1H), 3.96-3.87 (m, 1H), 2.82 (br t, J = 7.1 Hz, 2H), 2.69(br t, J = 7.0 Hz, 2H), 2.64 (br s, 1H), 2.40 (br dd, J = 22.0, 9.3 Hz,4H), 2.28-2.18 (m, 2H), 2.05 (br t, J = 10.0 Hz, 1H), 1.90-1.80 (m, 2H),0.57 (br d, J = 5.9 Hz, 2H), 0.53 (br s, 2H) 195

6-(3-hydroxypropyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3- carboxamide 458.2E: 1.19 F: 1.19 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.57 (br s, 1H), 8.50(s, 1H), 8.28 (br dd, J = 13.0, 7.4 Hz, 2H), 8.11 (br d, J = 8.9 Hz,1H), 7.97-7.91 (m, 1H), 7.91-7.87 (m, 2H), 7.87-7.82 (m, 1H), 7.37 (brd, J = 9.3 Hz, 1H), 4.38 (br d, J = 7.7 Hz, 2H), 3.97-3.87 (m, 2H),2.73-2.62 (m, 3H), 2.44-2.33 (m, 4H), 2.29-2.16 (m, 3H), 2.08-2.00 (m,1H), 1.80-1.70 (m, 2H) 196

6-(3-(4,4- difluoropiperidin-1- yl)propyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 561.4 E: 1.12 F: 1.58 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.50 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.31 (br d, J= 6.7 Hz, 1H), 8.25 (br d, J = 7.9 Hz, 1H), 8.09 (br d, J = 8.9 Hz, 1H),7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.38 (br d, J =9.2 Hz, 1H), 4.41-4.31 (m, 1H), 3.95-3.85 (m, 1H), 2.68- 2.59 (m, 4H),2.43-2.32 (m, 4H), 2.27-2.15 (m, 3H), 2.07-1.93 (m, 5H), 1.81 (br s, 2H)197

6-(3-(3,3- difluoropyrrolidin-1- yl)propyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 547.2 E: 1.61 F: 1.63 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.30 (br d, J= 7.5 Hz, 1H), 8.25 (br d, J = 7.8 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H),7.96-7.90 (m, 1H), 7.96-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m,1H), 7.38 (br d, J = 9.3 Hz, 1H), 4.43-4.32 (m, 1H), 3.91 (br t, J = 8.5Hz, 1H), 2.69 (br t, J = 7.3 Hz, 2H), 2.62 (br d, J = 16.0 Hz, 1H),2.59-2.52 (m, 3H), 2.44-2.32 (m, 3H), 2.28-2.17 (m, 2H), 2.04 (br t, J =10.0 Hz, 1H), 1.95 (br s, 2H)

Example 198:6-(3-hydroxy-3-methylbutyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

A solution of Intermediate 70 (20 mg, 0.042 mmol), 2-methylbut-3-en-2-ol(10.49 μl, 0.100 mmol), dihydrogendi-mu-chlorotetrakis(diphenylphosphinito-kp)dipalladate(2-) (2.3 mg,2.091 μmol) and sodium acetate (8.9 mg, 0.109 mmol) in anhydrous DMF (1mL) was degassed (3× vacuum/Ar) at rt, and then was stirred at 90° C.,for 16 h under Ar atmosphere. The reaction mixture was diluted withEtOAc (50 mL), washed with water (2×15 mL), brine (1×20 mL), and dried(Na₂SO₄). EtOAc was removed under reduced pressure and the residue wasdissolved in MeOH (5 mL). The reaction mixture was degassed (3×vacuum/Ar), then Pd—C (5% wt.) (4.5 mg, 4.2 μmol) was added. Thereaction mixture was degassed again, and was stirred under dihydrogengas (1 atm.) for 1 h at rt. The reaction mixture was degassed,additional amount of Pd—C (5% wt.) (4.5 mg, 4.2 μmol) was added, thereaction mixture was degassed again, and was stirred under dihydrogengas (1 atm.) for 14 h at rt. Pd—C was filtered off, and MeOH was removedunder reduced pressure. The residue was dissolved in DMF (2 mL), andpurified by preparative HPLC to afford Example 198 (7.1 mg, 35% yield).MS(ESI) m/z: 486.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.49 (s,1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.31-8.21 (m, 2H), 8.10 (br d, J=9.0Hz, 1H), 7.96-7.89 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.35(br d, J=9.3 Hz, 1H), 4.42-4.32 (m, 1H), 3.90 (quin, J=8.2 Hz, 1H),2.70-2.61 (m, 3H), 2.43-2.31 (m, 3H), 2.28-2.16 (m, 2H), 2.04 (br t,J=10.0 Hz, 1H), 1.73-1.62 (m, 2H), 1.15 (s, 6H). HPLC RT=E: 1.35 F:1.35.

Example 199:N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl)pyrazolo[1,5-a]pyridine-3-carboxamide

A solution of Intermediate 70 (20 mg, 0.042 mmol),1,1,1-trifluoro-2-(trifluoromethyl)but-3-en-2-ol (0.014 mL, 0.10 mmol),dihydrogen di-mu-chlorotetrakis(diphenylphosphinito-kp)dipalladate(2-)(2.3 mg, 2.1 μmol) and sodium acetate (8.9 mg, 0.11 mmol) in anhydrousDMF (1 mL) was degassed (3× vacuum/Ar) at rt, and then was stirred at90° C., for 16 h under Ar atmosphere. The reaction mixture was dilutedwith EtOAc (50 mL), washed with water (2×15 mL), brine (1×20 mL), anddried (Na₂SO₄). EtOAc was removed under reduced pressure and the residuewas dissolved in MeOH (5 mL). The reaction mixture was degassed (3×vacuum/Ar), then Pd—C (5% wt.) (4.5 mg, 4.2 μmol) was added. Thereaction mixture was degassed again, and stirred under dihydrogen gas (1atm.) for 1 h at rt. The reaction mixture was degassed, additionalamount of Pd—C (5% wt.) (4.5 mg, 4.2 μmol) was added, the reactionmixture was degassed again, and was stirred under dihydrogen gas (1atm.) for 14 h at rt. The reaction mixture was filtered through amembrane filter, degassed, Pd—C (5% wt.) (4.5 mg, 4.2 μmol) was added.The reaction mixture was degassed again, and stirred under dihydrogengas (1 atm.) for 20 h at rt. Pd—C was filtered off, and MeOH was removedunder reduced pressure. The residue was dissolved in DMF (2 mL), andpurified by preparative HPLC to afford Example 199 (0.9 mg, 4% yield).MS(ESI) m z: 594.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.69 (br s,1H), 8.51 (s, 1H), 8.31 (br d, J=6.6 Hz, 1H), 8.25 (br d, J=7.8 Hz, 1H),8.13 (br d, J=8.9 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H),7.86-7.81 (m, 1H), 7.43 (br d, J=8.8 Hz, 1H), 4.37 (br d, J=7.9 Hz, 2H),3.96-3.86 (m, 2H), 2.83 (br s, 2H), 2.62 (br s, 1H), 2.44-2.32 (m, 3H),2.22 (br d, J=9.0 Hz, 4H), 2.07-1.99 (m, 1H). HPLC RT=E: 1.72 F: 1.72.

Example 200:6-(morpholinomethyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

A pressure vial was charged with Intermediate 70, potassium(morpholinomethyl)trifluoroborate (13 mg, 0.063 mmol), RuPhos-Pd G3 (2.6mg, 3.1 μmol) and cesium carbonate (30.7 mg, 0.094 mmol). The mixturewas degassed (3×, vacuum/Ar). Then Dioxane (1 mL) and water (0.100 mL)were added, and the reaction mixture was degassed again. The pressurevial was capped, and the reaction mixture was stirred at 90° C., for 18h. The reaction mixture was acidified with TFA, solvent was removedunder reduced pressure, the residue was suspended in DMF, filtered, andpurified by preparative HPLC to give Example 200 (8.1 mg, 52% yield).MS(ESI) m/z; 498.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.43 (s,1H), 8.90 (s, 1H), 8.60 (s, 1H), 8.35 (br d, J=7.3 Hz, 1H), 8.21 (br t,J=8.5 Hz, 2H), 7.92-7.86 (m, 1H), 7.86-7.82 (m, 1H), 7.82-7.73 (m, 1H),7.50 (br d, J-=9.2 Hz, 1H), 4.39-4.29 (m, 3H), 3.87 (quin, J=8.3 Hz,1H), 2.60 (br s, 1H), 2.46 (br s, 6H), 2.41-2.28 (m, 3H), 2.25-2.14 (m,2H), 2.01 (br t, J=9.9 Hz, 1H). HPLC RT=E: 1.14 F: 1.44.

The following Examples in Table 13 were prepared by using a similarprocedure as shown in Example 200 by reacting Intermediate 70 with theappropriate potassium trifluoroborates/boronic acids/boronate esters.

TABLE 13 HPLC Method, Ex. R Name LCMS (M + H)⁺ RT (min.) ¹H NMR 201

6-((4-methylpiperazin-1- yl)methyl)-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 512.1 E: 1.10 F: 1.25 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.43 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.24 (br d, J= 7.3 Hz, 1H), 8.21 (br d, J = 7.9 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H),7.91-7.86 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.81-7.74 (m, 1H), 7.36 (brd, J = 8.9 Hz, 1H), 4.38-4.28 (m, 1H), 3.86 (br t, J = 8.4 Hz, 1H), 3.47(s, 1H), 2.59 (br s, 1H), 2.35 (br dd, J = 22.6, 9.2 Hz, 9H), 2.18 (brd, J = 9.5 Hz, 2H), 2.14 (s, 3H), 2.04-1.94 (m, 1H), 1.86 (s, 2H) 202

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(piperidin-1- ylmethyl)pyrazolo[1,5- a]pyridine-3-carboxamide 497.1 E:1.29 F: 1.44 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.44 (s, 1H), 8.91 (s,1H), 8.60 (s, 1H), 8.35 (br d, J = 7.6 Hz, 1H), 8.21 (br t, J = 9.5 Hz,2H), 7.92-7.86 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.82-7.76 (m, 1H),7.50 (br d, J = 8.9 Hz, 1H), 4.39-4.33 (m, 1H), 4.32 (br s, 2H), 3.87(quin, J = 8.3 Hz, 1H), 2.60 (br s, 1H), 2.56-2.51 (m, 1H), 2.46 (br s,6H), 2.41-2.28 (m, 3H), 2.25-2.14 (m, 2H), 2.01 (br t, J = 9.9 Hz, 1H),1.77 (br s, 2H), 1.61 (br s, 2H) 203

6-((dimethylamino)methyl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridin-3-carboxamide 457.1 E:1.22 F: 1.31 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 8.92 (s,1H), 8.60 (s, 1H), 8.36 (br d, J = 7.6 Hz, 1H), 8.21 (t, J = 8.1 Hz,2H), 7.92-7.86 (m, 1H), 7.85-7.82 (m, 1H), 7.82-7.76 (m, 1H), 7.50 (brd, J = 9.2 Hz, 1H), 4.38-4.33 (m, 1H), 4.32 (br s, 2H), 3.87 (br t, J =8.2 Hz, 1H), 2.74 (s, 6H), 2.60 (br s, 1H), 2.41-2.30 (m, 3H), 2.24-2.14(m, 2H), 2.01 (br t, J = 10.1 Hz, 1H) 204

6-benzyl-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 490.1E: 1.84 F: 2.02 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.67 (s,1H), 8.50 (s, 1H), 8.31-8.21 (m, 2H), 8.09 (br d, J = 9.2 Hz, 1H),7.96-7.89 (m, 1H), 7.89-7.85 (m, 1H), 7.85- 7.78 (m, 1H), 7.30 (br d, J= 4.3 Hz, 5H), 7.22 (br d, J = 4.3 Hz, 1H), 4.42-4.30 (m, 1H), 3.99 (s,2H), 3.90 (br t, J = 8.4 Hz, 1H), 2.62 (br s, 1H), 2.44-2.30 (m, 3H),2.27-2.14 (m, 2H), 2.04 (br t, J = 9.9 Hz, 1H) 205

6-(3-morpholino-3- oxopropyl)-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 541.1 E: 1.41 F: 1.38 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.43 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 8.22 (br d, J= 7.6 Hz, 2H), 8.05 (br d, J = 9.2 Hz, 1H), 7.92-7.86 (m, 1H), 7.86-7.82(m, 1H), 7.82-7.75 (m, 1H), 7.36 (br d, J = 9.2 Hz, 1H), 4.42-4.27 (m,1H), 3.86 (br t, J = 7.9 Hz, 1H), 3.47 (br s, 3H), 3.40 (br s, 1H),2.87-2.77 (m, 2H), 2.71-2.63 (m ,2H), 2.59 (br s, 1H), 2.46 (br s, 4H),2.41-2.27 (m, 3H), 2.25-2.12 (m, 2H), 2.05-1.96 (m, 1H) 206

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(3,3,3- trifluoropropyl)pyrazolo[1,5-a] pyridin-3- carboxamide 496.1E: 1.81 F: 1.81 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 8.68 (s,1H), 8.48 (s, 1H), 8.24 (br d, J = 7.6 Hz, 1H), 8.21 (br d, J = 7.9 Hz,1H), 8.08 (br d, J = 9.2 Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.82 (m, 1H),7.82-7.76 (m, 1H), 7.41 (br d, J = 9.5 Hz, 1H), 4.39-4.27 (m, 1H), 3.87(br t, J = 8.4 Hz, 1H), 2.89-2.81 (m, 2H), 2.70-2.56 (m, 3H), 2.56-2.51(m, 1H), 2.40-2.28 (m, 3H), 2.24-2.13 (m, 2H), 2.05-1.96 (m, 1H) 207

6-(2-cyanoethyl)-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 453.3E: 1.37 F: 1.43 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 8.68 (s,1H), 8.49 (s, 1H), 8.26 (br d, J = 7.3 Hz, 1H), 8.21 (br d, J = 7.9 Hz,1H), 8.10 (d, J = 9.2 Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.82 (m, 1H),7.82-7.73 (m, 1H), 7.40 (br d, J = 9.2 Hz, 1H), 4.38-4.28 (m, 1H), 3.87(br t, J = 8.4 Hz, 1H), 2.91 (br d, J = 6.4 Hz, 2H), 2.87 (br d, J = 6.4Hz, 2H), 2.64-2.56 (m, 1H), 2.56-2.51 (m, 1H), 2.44-2.28 (m, 3H),2.24-2.12 (m, 2H), 2.07-1.97 (m, 1H) 208

6-((2-morpholinoethoxy)methyl)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 543 E: 1.05 F: 1.22 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.50 (s, 1H), 8.80 (s, 1H), 8.57 (s, 1H), 8.34 (br d, J = 7.2 Hz,1H), 8.25 (d, J = 7.7 Hz, 1H), 8.19 (br d, J = 9.1 Hz, 1H), 7.97-7.90(m, 1H), 7.90-7.86 (m, 1H), 7.86-7.79 (m, 1H), 7.45 (br d, J = 9.3 Hz,1H), 4.59 (s, 2H), 4.43-4.31 (m, 1H), 3.96-3.85 (m, 2H), 2.69-2.60 (m,1H), 2.54 (s, 8H), 2.44-2.32 (m, 3H), 2.29- 2.17 (m, 2H), 2.04 (br t, J= 10.1 Hz, 1H) 209

6-(methoxymethyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 444.3E: 1.38 F: 1.28 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.72 (s,1H), 8.55 (s, 1H), 8.33 (br d, J = 7.4 Hz, 1H), 8.25 (br d, J = 7.9 Hz,1H), 8.16 (br d, J = 9.1 Hz, 1H), 7.41 (br d, J = 9.1 Hz, 1H), 4.46 (s,2H), 4.42-4.30 (m, 1H), 3.90 (br t, J = 8.4 Hz, 1H), 3.48 (br s, 3H),2.68-2.56 (m, 2H), 2.44-2.30 (m, 3H), 2.28-2.15 (m, 2H), 2.04 (br t, J =10.0 Hz, 1H) 210

6-(2-methoxypyrimidin-5- yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5- a]pyridine-3-carboxamide 508.1E: 1.46 F: 1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.25 (s,1H), 9.05 (s, 2H), 8.62 (s, 1H), 8.36 (br d, J = 7.3 Hz, 1H), 8.30-8.21(m, 2H), 7.97-7.81 (m, 4H), 4.44-4.35 (m, 1H), 3.98 (s, 3H), 3.95-3.85(m, 1H), 2.69-2.55 (m, 2H), 2.45-2.33 (m, 3H), 2.30-2.17 (m, 2H), 2.07(br t, J = 10.1 Hz, 1H) 211

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(((tetrahydro-2H-pyran- 4-yl)methoxy)methyl)pyraz-olo[1,5-a]pyridine-3- carboxamide 528.2 E: 1.57 F: 1.63 ¹H NMR: (500MHz, DMSO-d₆) δ ppm 12.43 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.26 (brd, J = 7.6 Hz, 1H), 8.22 (br d, J = 7.6 Hz, 1H), 8.13 (br d, J = 9.2 Hz,1H), 7.93-7.86 (m, 1H), 7.86-7.82 (m, 1H), 7.82-7.75 (m, 1H), 7.37 (brd, J = 9.2 Hz, 1H), 4.47 (s, 2H), 4.39-4.25 (m, 1H), 3.87 (br t, J = 8.2Hz, 1H), 3.32-3.17 (m, 2H), 2.59 (br s, 1H), 2.41- 2.28 (m, 3H),2.25-2.12 (m, 2H), 2.06-1.97 (m, 1H), 1.78 (br s, 1H), 1.54 (br d, J =12.8 Hz, 2H), 1.23-1.05 (m, 2H)

Example 212:6-((allyloxy)methyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Example 212A: methyl6-((allyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

A pressure vial was charged with methyl6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 0.784 mmol),potassium (allyloxy)methyltrifluoroborate (181 mg, 1.02 mmol), RuPhos-PdG2 (30.5 mg, 0.039 mmol) and cesium carbonate (766 mg, 2.35 mmol). Themixture was degassed (3×, vacuum/Ar). Then dioxane (4 mL) and water (0.4mL) were added, and the reaction mixture was degassed again. Thepressure vial was capped, and the reaction mixture was stirred at 110°C., for 18 h. The reaction mixture was diluted with EtOAc (100 mL), andCELITE® was added. Solvent was removed under reduced pressure and theresidue was purified by flash chromatography (solid loading on CELITE®)to give Example 212A (112 mg, 58% yield) as a colorless oil. MS(ESI)m/z; 247.0 (M+H)⁺, H NMR (500 MHz, DMSO-d₆) δ ppm 8.84 (d, J=0.8 Hz,1H), 8.45 (s, 1H), 8.07 (dd, J=9.1, 0.8 Hz, 1H), 7.60 (dd, J=9.1, 1.4Hz, 1H), 5.95 (ddt, J=17.3, 10.6, 5.3 Hz, 1H), 5.31 (dq, J=17.2, 1.8 Hz,1H), 5.19 (dq, J=10.5, 1.6 Hz, 1H), 4.57 (s, 2H), 4.05 (dt, J=5.4, 1.4Hz, 2H), 3.83 (s, 3H).

Example 212B: 6-((allyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Example 212A (112 mg, 0.455 mmol) was dissolved in MeOH (1.5 mL)/THF(1.5 mL), and LiOH (1 M aq.) (1.364 mL, 1.364 mmol) was added. Thereaction mixture was stirred under microwave irradiation at 120° C., for15 min. The reaction mixture was acidified with TFA, diluted with MeOH,and was purified by preparative HPLC to afford Example 212B (53 mg, 50%yield) as a white solid. MS(ESI) m/z: 233.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.45 (br s, 1H), 8.81 (s, 1H), 8.38 (s, 1H), 8.06 (d,J=9.1 Hz, 1H), 7.55 (dd, J=9.1, 1.1 Hz, 1H), 5.94 (ddt, J=17.2, 10.5,5.4 Hz, 1H), 5.31 (dq, J=17.3, 1.7 Hz, 1H), 5.18 (dq, J=10.5, 1.6 Hz,1H), 4.56 (s, 2H), 4.04 (dt, J=5.4, 1.4 Hz, 2H).

Example 212

Example 212 was prepared according to the procedure described in Example14 to afford Example 212 (73 mg, 68% yield) as a colorless glass, whichsolidified upon standing. MS(ESI) m/z: 470.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.46 (s, 1H), 8.74-8.68 (m, 1H), 8.55 (s, 1H), 8.32-8.23(m, 2H), 8.17 (dd, J=9.1, 0.8 Hz, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m,1H), 7.86-7.80 (m, 1H), 7.43 (dd, J=9.2, 1.5 Hz, 1H), 5.94 (ddt, J=17.2,10.5, 5.4 Hz, 1H), 5.30 (dq, J=17.3, 1.7 Hz, 1H), 5.18 (dq, J=10.5, 1.6Hz, 1H), 4.53 (s, 2H), 4.44-4.31 (m, 1H), 4.06-4.00 (m, 3H), 3.91 (quin,J=8.5 Hz, 1H), 2.68-2.55 (m, 2H), 2.46-2.33 (m, 3H), 2.29-2.17 (m, 2H).

Example 213:6-(hydroxymethyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Example 212 (15 mg, 0.032 mmol) was dissolved in THF (0.5 mL) and MeOH(1.5 mL), then Pd(PPh₃)₄ (9.2 mg, 8.0 μmol) was added. The slightlyyellow solution was stirred at rt for 5 min, then potassium carbonate(13 mg, 0.0% mmol) was added. The reaction mixture was stirred at 60°C., for 3 h. The reaction mixture was acidified with TFA. Solvent wasremoved under reduced pressure, the residue was diluted with DMF,filtered, and purified by preparative HPLC to afford Example 213 (12.3mg, 90% yield). MS(ESI) m/z: 429.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δppm 12.43 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.22 (br t, J=7.6 Hz,2H), 8.11 (br d, J=9.2 Hz, 1H), 7.92-7.86 (m, 1H), 7.86-7.82 (m, 1H),7.82-7.75 (m, 1H), 7.37 (br d, J=8.9 Hz, 1H), 4.51 (br d, J=5.5 Hz, 2H),4.39-4.28 (m, 1H), 3.87 (br t, J=8.4 Hz, 1H), 2.60 (br s, 1H), 2.41-2.28(m, 3H), 2.26-2.13 (m, 2H), 2.06-1.96 (m, 1H). HPLC RT=E: 1.28 F: 1.26.HPLC RT=E: 1.66 F: 1.64.

Example 214:6-acetyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Intermediate 70 (50 mg, 0.105 mmol) and Pd-XPhos G3 (6.6 mg, 7.8 μmol)were placed in a pressure vial. Then THF (2 mL) andtributyl(1-ethoxyvinyl)stannane (0.106 mL, 0.314 mmol) were added, andthe reaction mixture was degassed (3×, vacuum/Ar). The pressure vial wascapped, and the reaction mixture was stirred at 120° C., for 30 min.Most of the solvent was removed under reduced pressure, the obtainedresidue was dissolved with wet MeOH (2 mL), and TFA (0.040 mL, 0.52mmol) was added. The reaction mixture was heated at 50° C., for 5 min.Solvent was removed under reduced pressure, the residue was purified bypreparative HPLC to afford Example 214 (23 mg, 49% yield). MS(ESI) m/z:442.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.46 (s, 1H), 9.51 (s,1H), 8.74 (s, 1H), 8.41 (d, J=7.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.22(d, J=9.4 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.79 (m,2H), 4.39 (dq, J=16.0, 8.0 Hz, 1H), 3.91 (quin, J=8.5 Hz, 1H), 2.65 (s,3H), 2.61-2.54 (m, 1H), 2.46-2.36 (m, 3H), 2.29-2.20 (m, 2H), 2.10-2.02(m, 1H). HPLC RT=E: 1.46 F: 1.47. HPLC RT=A: 6.89 B: 7.14.

Example 215:6-(2-hydroxypropan-2-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Methylmagnesium bromide (3 M in Et₂O) (0.076 mL, 0.23 mmol) was added toanhydrous THF (1 mL), and the reaction mixture was cooled to 0° C. Tothis mixture, a solution/suspension of Example 214 (10 mg, 0.023 mmol)in anhydrous THF (1 mL), was added in one portion. The reaction mixturewas stirred at 0° C., for 15 min, and then was allowed to reach rtwithin 1 h. Additional amount of methylmagnesium bromide (3 M in Et₂O)(0.076 mL, 0.227 mmol) was added, and the reaction mixture was stirredat rt for additional 16 h. The reaction mixture was cooled to rt, andquenched with MeOH (1 mL). Solvent was removed under reduced pressure,the residue was triturated with DMF (2 mL), filtered, and purified bypreparative HPLC to afford Example 215 (3.5 mg, 34% yield) was obtained.MS(ESI) m/z: 458.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-dt) δ ppm 12.47 (s,1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.26 (br t, J=8.7 Hz, 2H), 8.11 (d,J=9.2 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.85 (m, 1H), 7.85-7.79 (m, 1H),7.56 (br d, J=9.5 Hz, 1H), 4.43-4.31 (m, 1H), 3.95-3.85 (m, 1H), 2.63(br s, 1H), 2.44-2.31 (m, 4H), 2.28-2.17 (m, 3H), 2.09-2.01 (m, 1H),1.48 (s, 6H). HPLC RT=E: 1.46 F: 1.47.

Example 216:6-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Intermediate 70 (15 mg, 0.031 mmol),1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(20.9 mg, 0.094 mmol) and Pd-XPhos G3 (2.0 mg, 2.4 μmol) were placed ina pressure vial. Then THF (1.25 mL) and Phosphoric acid, potassium salt(0.5 M aq.) (0.125 mL, 0.063 mmol) were added, and the reaction mixturewas degassed (3×, vacuum/Ar). The pressure vial was capped, and thereaction mixture was stirred at 120° C., for 30 min. Most of the solventwas removed under reduced pressure, the obtained residue was dilutedwith DMF (2 mL), filtered and purified by preparative HPLC to provideExample 216 (14.6 mg, 87% yield) was obtained. MS(ESI) m/z: 494.0(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.71 (s, 1H),8.54 (s, 1H), 8.30 (br d, J=7.6 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 8.18(d, J=9.2 Hz, 1H), 8.03 (s, 1H), 7.97-7.90 (m, 1H), 7.90-7.86 (m, 1H),7.86-7.80 (m, 1H), 7.56 (d, 1-9.2 Hz, 1H), 4.45-4.32 (m, 1H), 3.91(quin, J=8.4 Hz, 1H), 3.80 (s, 3H), 2.68-2.61 (m, 1H), 2.60-2.55 (m,1H), 2.45-2.35 (m, 3H), 2.33 (s, 3H), 2.29-2.14 (m, 2H), 2.06 (br t,J=10.1 Hz, 1H). HPLC RT=E: 1.50 F: 1.53.

The following Examples in Table 14 were prepared by using a similarprocedure as shown in Example 216 by reacting Intermediate 70 with theappropriate boronic acids/boronate esters/potassium trifluoroborates.

TABLE 14 Ex. R Name LCMS (M + H)⁺ HPLC Method, RT (min.) ¹H NMR 217

6-(1-cyclopropyl-1H- pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 506 E: 1.62 F: 1.63 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.38(s, 1H), 8.29 (br d, J = 7.3 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.16 (d,J = 9.2 Hz, 1H), 8.01 (s, 1H), 7.96-7.90 (m, 1H), 7.89-7.86 (m, 1H),7.86- 7.80 (m, 1H), 7.73 (d, J = 9.2 Hz, 1H), 4.43-4.32 (m, 1H),3.96-3.86 (m, 1H), 3.75 (tt, J = 7.3, 3.7 Hz, 1H), 2.69-2.61 (m, 1H),2.58 (br t, J = 7.9 Hz, 1H), 2.47-2.33 (m, 3H), 2.29-2.18 (m, 2H), 2.05(br t, J = 10.1 Hz, 1H), 1.11-1.04 (m, 2H), 1.02-0.94 (m, 2H) 218

6-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 520.1 E: 1.70 F: 1.71 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm9.06 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.29 (br d, J = 7.6 Hz, 1H),8.26 (br d, J = 7.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H),7.96- 7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.80 (m, 1H), 7.73 (d, J =9.5 Hz, 1H), 4.44-4.33 (m, 1H), 4.00 (d, J = 7.0 Hz, 2H), 3.91 (quin, J= 8.5 Hz, 1H), 2.68-2.61 (m, 1H), 2.58 (br t, J = 8.1 Hz, 1H), 2.45-2.33(m, 3H), 2.28-2.18 (m, 2H), 2.06 (br t, J = 10.1 Hz, 1H), 1.31-1.24 (m,1H), 0.56 (br d, J = 7.9 Hz, 2H), 0.40 (br d, J = 4.9 Hz, 2H) 219

6-(1-((²H₃)methyl-1H- pyraozl-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 483 E: 1.49 F: 1.49 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.03 (s, 1H), 8.52 (s, 1H), 8.29(br d, J = 7.6 Hz, 1H), 8.27-8.22 (m, 2H), 8.17 (d, J = 9.2 Hz, 1H),8.01 (s, 1H), 7.95-7.90 (m, 1H), 7.90-7.86 (m, 1H), 7.86-7.80 (m, 1H),7.70 (d, J = 9.5 Hz, 1H), 4.44-4.33 (m, 1H), 3.91 (quin, J = 8.4 Hz,1H), 2.68-2.62 (m, 1H), 2.61-2.55 (m, 1H), 2.45-2.32 (m, 3H), 2.30-2.17(m, 2H), 2.06 (br t, J = 9.9 Hz, 1H) 220

6-(1-isopropyl-1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 508.3 E: 1.58 F: 1.53 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.05 (s, 1H), 8.38 (s, 1H), 8.32(br d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 9.1 Hz,1H), 8.02 (s, 1H), 7.95- 7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.81 (m,1H), 7.74 (br d, J = 9.3 Hz, 1H), 4.51 (dt, J = 13.3, 6.6 Hz, 1H), 4.43-4.32 (m, 1H), 3.91 (quin, J = 8.4 Hz, 1H), 2.67-2.60 (m, 1H), 2.60-2.55(m, 1H), 2.45-2.32 (m, 3H), 2.28-2.17 (m, 2H), 2.05 (br t, J = 10.1 Hz,1H), 1.45 (d, J = 6.6 Hz, 6H) 221

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1,3,5-trimethyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide 508.3 E: 1.35 F: 1.41 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.33 (d, J =7.6 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H),7.96-7.90 (m, 1H), 7.90- 7.86 (m, 1H), 7.86-7.81 (m, 1H), 7.39 (d, J =9.9 Hz, 1H), 4.44-4.33 (m, 1H), 3.95-3.85 (m, 1H), 3.71 (s, 3H), 2.64(br t, J = 11.5 Hz, 1H), 2.61-2.55 (m, 1H), 2.45-2.32 (m, 3H), 2.24 (s,4H), 2.15 (s, 3H), 2.05 (br t, J = 10.0 Hz, 1H) 222

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1-(tetrahydro-2H-pyran- 4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 550.2 E: 1.54 F: 1.59 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.42(s, 1H), 8.30 (br d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.16 (d,J = 9.2 Hz, 1H), 8.05 (s, 1H), 7.95-7.89 (m, 1H), 7.89-7.86 (m, 1H),7.86- 7.80 (m, 1H), 7.74 (d, J = 9.5 Hz, 1H), 4.46-4.32 (m, 2H), 3.97(br d, J = 9.2 Hz, 2H), 3.91 (quin, J = 8.5 Hz, 1H), 3.53- 3.45 (m, 1H),2.68-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.45- 2.32 (m, 3H), 2.28-2.18 (m,2H), 2.09-2.00 (m, 3H), 1.99-1.88 (m, 2H) 223

6-(1-methyl-3- (trifluoromethyl)-1H- pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 548.1 E: 1.75 F: 1.80 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 8.37(br d, J = 7.6 Hz, 1H), 8.27 (s, 1H), 8.26-8.24 (m, 1H), 8.22 (d, J =9.2 Hz, 1H), 7.95- 7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H),7.45 (br d, J = 8.9 Hz, 1H), 4.44-4.33 (m, 1H), 3.98 (s, 3H), 3.91 (brt, J = 8.4 Hz, 1H), 2.68-2.62 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.32 (m,3H), 2.30-2.18 (m, 2H), 2.05 (br t, J = 9.9 Hz, 1H) 224

6-(1-isopropyl-3- (trifluoromethyl)-1H- pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyraozlo[1,5-a]pyridine- 3-carboxamide 576.1 E: 1.97 F: 2.03 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.42(s, 1H), 8.36 (br d, J = 7.6 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.23 (d,J = 9.2 Hz, 1H), 7.91 (br d, J = 7.0 Hz, 1H), 7.89-7.86 (m, 1H),7.85-7.79 (m, 1H), 7.49 (br d, J = 9.2 Hz, 1H), 4.64 (dt, J = 13.2, 6.7Hz, 1H), 4.44-4.33 (m, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.68- 2.61 (m,1H), 2.61-2.55 (m, 1H), 2.46-2.32 (m, 3H), 2.29- 2.18 (m, 2H), 2.06 (brt, J = 10.1 Hz, 1H), 1.50 (d, J = 6.4 Hz, 6H) 225

6-(1-tert-butyl)-1H- pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 522.2 E: 1.76 F: 1.83 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 9.07 (s, 1H), 8.52 (s, 1H), 8.46(s, 1H), 8.29 (br d, J = 7.3 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.16 (d,J = 9.2 Hz, 1H), 8.04 (s, 1H), 7.96-7.89 (m, 1H), 7.90-7.86 (m, 1H),7.85- 7.80 (m, 1H), 7.77 (d, J = 9.2 Hz, 1H), 4.43-4.32 (m, 1H), 3.91(quin, J = 8.5 Hz, 1H), 2.64 (br t, J = 11.4 Hz, 1H), 2.60- 2.55 (m,1H), 2.45-2.32 (m, 3H), 2.30-2.17 (m, 2H), 2.06 (br t, J = 10.1 Hz, 1H),1.56 (s, 9H) 226

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1-(tetrahydrofuran-3- yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carboxamide 536.1 E: 1.50 F: 1.57 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm12.47 (s, 1H), 9.07 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.30 (br d, J =7.3 Hz, 1H), 8.25 (br d, J = 7.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.07(s, 1H), 7.95-7.89 (m, 1H), 7.90-7.86 (m, 1H), 7.86- 7.80 (m, 1H), 7.74(br d, J = 9.2 Hz, 1H), 5.03 (br s, 1H), 4.43-4.33 (m, 1H), 4.04-3.97(m, 2H), 3.96-3.88 (m, 2H), 3.86-3.79 (m, 1H), 2.64 (br t, J = 11.3 Hz,1H), 2.60- 2.56 (m, 1H), 2.46-2.36 (m, 4H), 2.35-2.28 (m, 1H), 2.28-2.18(m, 2H), 2.05 (br t, J = 10.1 Hz, 1H)

Example 227.1-(4-bromophenyl)-3-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)urea

To a suspension of Intermediate 2, HCl (200 mg, 0.685 mmol) in THF (15mL), was added DIEA (0.299 mL, 1.71 mmol). The reaction mixture wascooled to 0° C., and 4-nitrophenyl carbonochloridate (166 mg, 0.823mmol) was added in one portion. The reaction mixture was stirred at 0°C., for 30 min. Then, 4-bromoaniline (236 mg, 1.37 mmol) and DIEA (0.299mL, 1.714 mmol) were added, cooling bath was removed, and the reactionmixture was stirred at 50° C., for 16 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified byflash chromatography (40-100% EtOAc/DCM gradient) to afford Example 227(244 mg, 79% yield) as a white solid. MS(ESI) m/z: 453.0 (M+H)⁺; ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.48 (s, 1H), 8.24 (br d, J=7.6Hz, 1H), 7.93-7.87 (m, 1H), 7.86-7.79 (m, 2H), 7.39-7.28 (m, 4H), 6.43(br d, J=7.6 Hz, 1H), 4.08-3.97 (m, 1H), 3.86 (quin, J=8.4 Hz, 1H), 2.58(br s, 1H), 2.41-2.27 (m, 3H), 2.23-2.14 (m, 1H), 1.99 (br t J=9.6 Hz,1H), 1.82 (br t, J=9.9 Hz, 1H); HPLC RT=1.79 min (E), 1.86 min (F).

The following Examples in Table 15 were prepared by using a similarprocedure as shown in Example 216 by reacting Example 227 with theappropriate boronic acids/boronate esters/potassium trifluoroborates.

TABLE 15 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 228

1-(4-(1-methyl-1H- pyrazol-4-yl)phenyl)- 3-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)urea 455.4 E: 1.37 F:1.35 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.31 (s, 1H), 8.25(d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.93-7.89 (m, 1H), 7.86 (br d, J =9.3 Hz, 1H), 7.84-7.80 (m, 1H), 7.74 (s, 1H), 7.42-7.37 (m, 2H),7.36-7.30 (m, 2H), 6.37 (d, J = 7.8 Hz, 1H), 4.05 (sxt, J = 8.0 Hz, 1H),3.93-3.85 (m, 1H), 3.83 (s, 3H), 2.66-2.57 (m, 1H), 2.41-2.28 (m, 3H),2.26-2.17 (m, 1H), 2.00 (br t, J = 9.6 Hz, 1H), 1.86-1.78 (m, 1H) 229

1-(4-(1-(²H₃)methyl-1H- pyrazol-4-yl)phenyl)- 3-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 458.2 E: 1.32 F: 1.33 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 7.99 (s, 1H), 7.94-7.89 (m, 1H), 7.88-7.80 (m, 2H), 7.74 (s,1H), 7.42-7.37 (m, 2H), 7.36- 7.31 (m, 2H), 6.37 (br d, J = 7.7 Hz, 1H),4.10-4.00 (m, 1H), 3.93-3.83 (m, 1H), 2.60 (br t, J = 11.4 Hz, 1H),2.41-2.29 (m, 3H), 2.25-2.17 (m, 1H), 2.00 (br t, J = 9.6 Hz, 1H), 1.82(br t, 2-yl)urea J = 9.8 Hz, 1H) 230

1-(4-(1-cyclopropyl-1H- pyrazol-4-yl) phenyl)-3-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 481.1 E: 1.47 F: 1.49 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 8.09 (s, 1H), 7.96-7.89 (m,1H), 7.88-7.80 (m, 2H), 7.74 (s,1H), 7.43-7.38 (m, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.37 (br d, J = 7.8Hz, 1H), 4.11-3.99 (m, 1H), 3.88 (quin, J = 8.5 Hz, 1H), 3.73-3.66 (m,1H), 2.64-2.56 (m, 2-yl)urea 1H), 2.41-2.28 (m, 3H), 2.25-2.16 (m, 1H),2.00 (br t, J = 9.8 Hz, 1H), 1.82 (br t, J = 9.8 Hz, 1H), 1.08-1.01 (m,2H), 0.98- 0.91 (m, 2H) 231

1-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3-(4-(1-(tetrahydro- 2H-pyran-4-yl)-1H- pyrazol-4-yl)phenyl)urea525.3 E: 1.41 F: 1.42 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.32 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.13 (s, 1H), 7.94-7.89 (m, 1H),7.88-7.81 (m, 2H), 7.78 (s, 1H), 7.45-7.40 (m, 2H), 7.34 (d, J = 8.6 Hz,2H), 6.37 (br d, J = 7.8 Hz, 1H), 4.37 (tt, J = 10.4, 5.1 Hz, 1H),4.11-4.00 (m, 1H), 3.96 (br d, J = 11.1 Hz, 2H), 3.88 (quin, J = 8.5 Hz,1H), 2.64-2.56 (m, 1H), 2.41-2.28 (m, 3H), 2.26-2.16 (m, 1H), 2.05-1.91(m, 5H), 1.87-1.77 (m, 1H) 232

1-(4-(1-methyl-3- (trifluoromethyl)- 1H-pyrazol-4-yl)phenyl)-3-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl) spiro[3.3]heptan-2-yl)urea523.2 E: 1.65 F: 1.65 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.44 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H), 7.94-7.89 (m, 1H),7.88-7.80 (m, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H),6.43 (br d, J = 7.7 Hz, 1H), 4.11-4.01 (m, 1H), 3.93 (s, 3H), 3.90-3.83(m, 1H), 2.64-2.57 (m, 1H), 2.42-2.29 (m, 3H), 2.25-2.17 (m, 1H), 2.01(br t, J = 9.6 Hz, 1H), 1.88-1.79 (m, 1H) 233

1-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3-(4-1,3,5- (trimethyl-1H-pyrazol-4- yl)phenyl)urea 483.3 E: 1.65 F:1.65 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.35 (s, 1H), 8.25(d, J = 7.8 Hz, 1H), 7.95-7.89 (m, 1H), 7.88-7.80 (m, 2H), 7.39 (d, J =8.5 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.39 (d, J = 7.9 Hz, 1H), 4.06(sxt, J = 8.0 Hz, 1H), 3.93-3.83 (m, 1H), 3.67 (s, 3H), 2.65-2.56 (m,1H), 2.41-2.28 (m, 3H), 2.25-2.18 (m, 1H), 2.17 (s, 3H), 2.08 (s, 3H),2.00 (br t, J = 9.6 Hz, 1H), 1.86-1.78 (m, 1H)

Example 234: 5-Bromo-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro3.3 heptan-2-yl)indoline-1-carboxamide

To a suspension of Intermediate 2, HCl (200 mg, 0.685 mmol) in THF (15mL), was added DIEA (0.299 mL, 1.71 mmol). The reaction mixture wascooled to 0° C., and 4-nitrophenyl carbonochloridate (166 mg, 0.823mmol) was added in one portion. The reaction mixture was stirred at 0°C., for 30 min. Then, 5-bromoindoline (272 mg, 1.37 mmol) and DIEA(0.299 mL, 1.71 mmol) were added, cooling bath was removed, and thereaction mixture was stirred at 50° C., for 16 h. The reaction mixturewas concentrated, and the residue was purified by flash chromatography(30-100% EtOAc/DCM gradient) to afford Example 234 (229 mg, 70% yield)as a white solid. MS(ESI) m/z: 479.0 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.48 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.98-7.91 (m, 1H),7.90-7.81 (m, 2H), 7.74 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.23 (br d,J=8.2 Hz, 1H), 6.78 (br d, J=7.3 Hz, 1H), 4.19-4.05 (m, 1H), 3.90 (br t,J=8.7 Hz, 3H), 3.11 (br t, J=8.7 Hz, 2H), 2.60 (br s, 1H), 2.43-2.29 (m,3H), 2.19 (q, J=9.8 Hz, 2H), 2.03 (br t. J=10.1 Hz, 1H); HPLC RT=1.97min (Method E), 2.04 min (Method F).

The following Examples in Table 16 were prepared by using a similarprocedure as shown in Example 216 by reacting Example 234 with theappropriate boronic acids/boronate esters/potassium trifluoroborates.

TABLE 16 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 235

5-(1-methyl-1H- pyrazol-4-yl)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)indoline-1-carboxamide481.3 E: 1.51 F: 1.55 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),8.25 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.95-7.89 (m, 1H), 7.89-7.80 (m,2H), 7.77-7.70 (m, 2H), 7.32 (s, 1H), 7.25 (br d, J = 8.3 Hz, 1H), 6.70(br d, J = 7.4 Hz, 1H), 4.18-4.06 (m, 1H), 3.93- 3.83 (m, 3H), 3.82 (s,3H), 3.09 (br t, J = 8.5 Hz, 2H), 2.58 (br s, 1H), 2.40-2.30 (m, 3H),2.23-2.12 (m, 2H), 2.06-1.97 (m, 1H) 236

5-(1-cyclopropyl- 1H-pyrazol-4-yl)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)indoline-1-carboxamide507.3 E: 1.66 F: 1.70 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),8.25 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.95-7.90 (m ,1H), 7.88-7.80 (m,2H), 7.77-7.71 (m, 2H), 7.35 (s, 1H), 7.27 (br d, J = 8.2 Hz, 1H), 6.70(br d, J = 7.5 Hz, 1H), 4.18-4.08 (m, 1H), 3.93- 3.83 (m, 4H), 3.68 (dt,J = 7.3, 3.6 Hz, 1H), 3.09 (br t, J = 8.6 Hz, 2H), 2.59 (br s, 1H),2.41-2.30 (m, 3H), 2.23-2.11 (m, 2H), 2.02 (br t, J = 10.0 Hz, 1H),1.06-1.01 (m, 2H), 0.98- 0.91 (m, 2H) 237

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(1,3,5-trimethyl-1H- pyrazol-4-yl)indoline- 1-carboxamide 509.4 E: 1.37F: 1.65 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J = 7.8Hz, 1H), 7.94-7.90 (m, 1H), 7.89-7.77 (m, 3H), 6.99 (s, 1H), 6.91 (br d,J = 8.2 Hz, 1H), 6.71 (br d, J = 7.5 Hz, 1H), 4.19-4.08 (m, 1H),3.94-3.84 (m, 3H), 3.11 (br t, J = 8.6 Hz, 2H), 2.61-2.55 (m, 1H),2.41-2.30 (m, 3H), 2.22-2.17 (m, 1H), 2.16 (s, 3H), 2.07 (s, 3H),2.05-1.97 (m, 1H) 238

5-(1-methyl-3- (trifluoromethyl)- 1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide 549.4 E: 1.81 F: 1.83 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.04 (s, 1H),7.94-7.90 (m, 1H), 7.89-7.78 (m, 3H), 7.14 (s, 1H), 7.09 (br d, J = 8.2Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 4.15 (sxt, J = 8.1 Hz, 1H), 3.92 (s,3H), 3.92- 3.85 (m, 3H), 3.12 (br t, J = 8.6 Hz, 2H), 2.60-2.55 (m, 1H),2.42-2.32 (m, 3H), 2.24-2.14 (m, 2H) 239

5-(1-(²H₃)methyl- 1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)indoline-1-carboxamide484.2 E: 1.46 F: 1.47 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.25 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.94-7.90 (m, 1H), 7.89-7.80 (m,2H), 7.76 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.26 (br d, J= 8.2 Hz, 1H), 6.69 (br d, J = 7.4 Hz, 1H), 4.20- 4.10 (m, 1H),3.93-3.84 (m, 3H), 3.10 (br t, J = 8.6 Hz, 2H), 2.59 (br s, 1H),2.41-2.31 (m, 3H), 2.23-2.12 (m, 2H), 2.06- 1.99 (m, 1H) 240

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(1-(tetrahydro- 2H-pyran-4-yl)- 1H-pyrazol-4-yl) 551.2 E: 1.59 F: 1.55¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J = 7.7 Hz,1H), 8.11 (s, 1H), 7.95-7.89 (m, 1H), 7.89-7.80 (m, 2H), 7.79-7.72 (m,2H), 7.36 (s, 1H), 7.28 (br d, J = 8.3 Hz, 1H), 6.70 (br d, J = 7.4 Hz,1H), 4.41-4.31 (m, 1H), 4.18- 4.08 (m, 1H), 3.95 (br d, J = 10.8 Hz,2H), indoline-1- 3.88 (td, J = 8.4, 4.2 carboxamide Hz, 3H), 3.13-3.05(m, 2H), 2.59 (br s, 1H), 2.41-2.29 (m, 3H), 2.22-2.13 (m, 2H),2.06-1.88 (m, 5H) 241

5-(1-(cyclopropyl- methyl)-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)indoline-1- carboxamide521.2 E: 1.75 F: 1.74 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H),8.25 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.95-7.90 (m, 1H), 7.89-7.80 (m,2H), 7.78-7.72 (m, 2H), 7.35 (s, 1H, 7.27 (br d, J = 8.3 Hz, 1H), 6.70(br d, J = 7.4 Hz, 1H), 4.13 (sxt, J = 7.9 Hz, 1H), 3.93 (d, J = 7.1 Hz,2H), 3.91-3.83 (m, 3H), 3.14-3.06 (m, 2H), 2.60-2.54 (m, 1H), 2.41-2.29(m, 3H), 2.23-2.13 (m, 2H), 2.05-1.98 (m, 1H), 1.28-1.19 (m, 1H),0.56-0.49 (m, 2H), 0.36 (br d, J = 5.0 Hz, 2H) 242

5-(1-(tert-butyl)- 1H-pyrazol-4- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)indoline-1- 523.2 E: 1.85F: 1.84 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J = 7.8Hz, 1H), 8.14 (s, 1H, 7.96-7.90 (m, 1H), 7.89-7.85 (m, 1H), 7.85-7.81(m, 1H), 7.76 (t, J = 4.1 Hz, 2H), 7.38 (s, 1H), 7.30 (br d, J = 8.3 Hz,1H), 6.69 (br d, J = 7.4 Hz, 1H), 4.13 (sxt, J = 8.1 Hz, 1H), 3.94-3.83(m, 3H), carboxamide 3.10 (br t, J = 8.6 Hz, 2H), 2.61-2.54 (m, 1H),2.41-2.29 (m, 3H), 2.23-2.12 (m, 2H), 2.05-1.97 (m, 1H), 1.52 (s, 9H)243

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(1-(tetrahydrofuran- 3-yl)-1H-pyrazol-4- yl)indoline-1- 537.4 E:1.57 F: 1.54 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J= 7.7 Hz, 1H), 8.09 (s, 1H), 7.95-7.90 (m, 1H), 7.89-7.85 (m, 1H),7.85-7.81 (m, 1H), 7.79 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H),7.29 (br d, J = 8.4 Hz, 1H), 6.70 (br d, J = 7.3 Hz, 1H), 5.02-4.94 (m,1H), carboxamide 4.19-4.08 (m, 1H), 4.02-3.94 (m, 2H), 3.93-3.84 (m,4H), 3.84-3.77 (m, 1H), 3.10 (br t, J = 8.5 Hz, 2H), 2.61-2.54 (m, 1H),2.43-2.32 (m, 4H), 2.32- 2.24 (m, 1H), 2.20-2.11 (m, 2H), 2.02 (br t, J= 10.1 Hz, 1H) 244

5-(1-isopropyl-3- (trifluoromethyl)- 1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)indoline-1-carboxamide 577.3 E: 2.00 F: 2.05 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H),7.95-7.89 (m, 1H), 7.87 (s, 1H), 7.85-7.81 (m, 1H), 7.80 (d, J = 8.3 Hz,1H), 7.17 (s, 1H), 7.11 (br d, J = 8.2 Hz, 1H), 6.77 (br d, J = 7.3 Hz,1H), 4.57 (dt, J = 13.3, 6.6 Hz, 1H), 4.18-4.07 (m, 1H), 3.95-3.83 (m,3H), 3.12 (br t, J = 8.6 Hz, 2H), 2.61-2.55 (m, 1H), 2.40-2.28 (m, 3H),2.18 (q, J = 9.5 Hz, 2H), 2.05-1.98 (m, 1H), 1.45 (d, J = 6.6 Hz, 6H)245

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(3,3,3-trifluoropropyl) 497.3 E: 2.00 F: 2.00 ¹H NMR: (500 MHz, DMSO-d₆)δ ppm 12.49 (s, 1H), 8.24 (br d, J = 7.7 Hz, 1H), 7.95-7.89 (m, 1H),7.87-7.79 (m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.94 (br d, J= 8.0 Hz, indoline- 1H), 6.68 (br d, J = 7.2 Hz, 1H), 4.15-4.03 (m, 1H),3.04 (br t, 1-carboxamide J = 8.5 Hz, 2H), 2.94-2.79 (m, 1H), 2.73-2.65(m, 2H), 2.49- 2.41 (m, 3H), 2.38-2.24 (m, 3H), 2.14 (br t, J = 9.6 Hz,2H), 1.97 (br t, J = 10.0 Hz, 1H)

The following Examples in Table 17 were prepared by using a similarprocedure as shown in Example 216 by reacting Intermediate 74 with theappropriate boronic acids/boronate esters/potassium trifluoroborates.

TABLE 17 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 246

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol- 4-yl)isoindoline-2- carboxamide 509.4 E:1.33 F: 1.52 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J= 7.8 Hz, 1H), 7.96-7.89 (m, 1H), 7.89-7.78 (m, 2H), 7.34 (d, J = 7.7Hz, 1H), 7.19-7.09 (m, 2H), 6.48 (br d, J = 7.7 Hz, 1H), 4.59 (br s,2H), 4.59 (br s, 2H), 4.16-4.05 (m, 1H), 3.88 (quin, J = 8.5 Hz, 1H),3.68 (s, 3H), 2.58-2.55 (m, 1H), 2.39-2.31 (m, 3H), 2.19 (s, 3H),2.18-2.12 (m, 2H), 2.10 (s, 3H), 1.97 (br t, J = 10.0 Hz, 1H) 247

5-(1-cyclopropyl-1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)isoindoline-2-carboxamide507.4 E: 1.58 F: 1.59 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.25 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 7.96-7.90 (m, 1H), 7.88-7.80 (m,3H), 7.52-7.45 (m, 2H), 7.27 (d, J = 7.8 Hz, 1H), 6.49 (br d, J = 7.7Hz, 1H), 4.56 (br s, 2H), 4.54 (br s, 2H), 4.10 (sxt, J = 8.1 Hz, 1H),3.88 (quin, J = 8.5 Hz, 1H), 3.72 (tt, J = 7.3, 3.8 Hz, 1H), 2.57 (br s,1H), 2.39-2.28 (m, 3H), 2.15 (br t, J = 9.7 Hz, 2H), 1.98 (br t, J =10.0 Hz, 1H), 1.09-1.03 (m, 2H), 0.99-0.93 (m, 2H) 248

5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)isoindoline-2-carboxamide543.9 E: 1.69 F: 1.69 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.25 (d, J = 7.8Hz, 1H), 8.12 (s, 1H), 7.96-7.89 (m, 1H), 7.88-7.85 (m, 1H), 7.85-7.80(m, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.30-7.27 (m, 1H), 6.50(br d, J = 7.7 Hz, 1H), 4.59 (s, 4H), 4.15-4.05 (m, 1H), 3.94 (s, 3H),3.88 (quin, J = 8.4 Hz, 1H), 2.57 (br s, 1H), 2.39-2.31 (m, 3H),2.18-2.12 (m, 2H), 2.01-1.94 (m, 1H) 249

5-(1-isopropyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)isoindoline-2-carboxamide 578.1 E: 1.92 F: 1.97 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.48 (s, 1H), 8.27-8.20 (m, 2H), 7.95-7.89 (m, 1H),7.88-7.85 (m, 1H), 7.85-7.79 (m, 1H), 7.40-7.36 (m, 1H), 7.34 (s, 1H),7.33-7.28 (m, 1H), 6.51 (d, J = 7.7 Hz, 1H), 4.64- 4.55 (m, 4H),4.15-4.05 (m, 1H), 3.88 (quin, J = 8.5 Hz, 1H), 2.57 (br s, 1H),2.40-2.30 (m, 3H), 2.20-2.11 (m, 2H), 1.97 (t, J = 10.0 Hz, 1H), 1.47(d, J = 6.6 Hz, 6H) 250

5-(1-methyl-1H-pyrazol-4- yl)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)isoindoline-2-carboxamide 481.1 E: 1.39 F:1.40 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.25 (d, J = 7.9Hz, 1H), 8.12 (s, 1H), 7.97-7.88 (m, 1H), 7.88-7.78 (m, 3H), 7.51-7.41(m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 6.48 (br d, J = 7.7 Hz, 1H), 4.57 (brs, 2H), 4.54 (br s, 2H), 4.10 (sxt, J = 8.2 Hz, 1H), 3.92- 3.86 (m, 1H),3.85 (s, 3H), 2.60-2.55 (m, 1H), 2.39- 2.28 (m, 3H), 2.15 (br t, J = 9.8Hz, 2H), 1.98 (br t, J = 10.0 Hz, 1H) 251

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(1-(tetrahydro-2H-pyran-4- yl)-1H-pyrazol-4-yl)isoindoline-2-carboxamide 551.5 E: 1.51 F: 1.51 ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.28-8.22 (m, 2H), 7.95-7.90 (m, 1H),7.89-7.78 (m, 3H), 7.55-7.45 (m, 2H), 7.28 (br d, J =7.8 Hz, 1H), 6.50(br d, J = 7.6 Hz, 1H), 4.57 (br s, 2H), 4.54 (br s, 2H), 4.38 (td, J =10.5, 5.4 Hz, 1H), 4.17-4.03 (m, 1H), 3.88 (br t, J = 8.5 Hz, 1H),3.53-3.39 (m, 1H), 2.60-2.55 (m, 1H), 2.41-2.26 (m, 3H), 2.15 (br t, J =9.5 Hz, 2H), 2.03-1.81 (m, 6H) 252

5-(1-(tert-butyl)-1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)isoindoline-2-carboxamide523.2 E: 1.73 F: 1.76 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H),8.28-8.23 (m, 2H), 7.95-7.89 (m, 1H), 7.88-7 79 (m, 3H), 7.56-7.48 (m,2H), 7.27 (d, J = 7.9 Hz, 1H), 6.49 (br d, J = 7.7 Hz, 1H), 4.57 (br s,2H), 4.55 (br s, 2H), 4.15-4.04 (m, 1H), 3.93-3.83 (m, 1H), 2.57 (br s,1H), 2.39-2.28 (m, 3H), 2.15 (br t, J = 9.8 Hz, 2H), 1.98 (br t, J =10.0 Hz, 1H), 1.54 (s, 9H) 253

5-(1-(²H₃)methyl-1H-pyrazol- 4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)isoindoline-2-carboxamide484.3 E: 1.39 F: 1.40 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.53-12.45 (m,1H), 12.48 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.95-7.81(m, 4H), 7.51-7.41 (m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 6.49 (br d, J =7.7 Hz, 1H), 4.56 (br s, 2H), 4.54 (br s, 2H), 4.14-4.06 (m, 1H), 3.92-3.82 (m, 1H), 2.39-2.29 (m, 3H), 2.15 (br t, J = 9.6 Hz, 2H), 1.98 (brt, J = 9.9 Hz, 1H)

The following Examples in Table 18 were prepared by using a similarprocedure as shown in Example 50 by reacting Example 50A with theappropriate amine.

TABLE 18 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 255

3,3-dimethyl-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)indoline-1- carboxamide 429.0 E: 1.84 F: 1.84¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.50 (s, 1H), 8.25 (d, J = 7.8 Hz,1H), 7.95-7 90 (m, 1H), 7.89-7.81 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H),7.15 (d, J = 7.3 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.87 (t, J = 7.4 Hz,1H), 6.74 (br d, J = 7.4 Hz, 1H), 4.17-4.06 (m, 1H), 3.89 (quin, J = 8.4Hz, 1H), 2.91 (br d, J = 5.2 Hz, 1H), 2.61-2.56 (m, 1H), 2.41-2.28 (m,3H), 2.21-2.11 (m, 2H), 2.00 (br t, J = 10.0 Hz, 1H), 1.26 (d, J = 2.5Hz, 6H), 1.16 (t, J = 7.3 Hz, 1H) 256

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine- 1-carboxamide 402.1 E: 1.18F: 1.63 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 9.20 (d, J = 7.5Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H), 7.94- 7.89(m, 1H), 7 87-7.79 (m, 2H), 7.56 (br d, J = 7.1 Hz, 1H), 6 86 (dd, J =7.1, 5.5 Hz, 1H), 4.22-4.10 (m, 1H), 3.94-3.82 (m, 3H), 3.01 (br t, J =8.6 Hz, 2H), 2.70-2.60 (m, 1H), 2.36 (br t, J = 8.8 Hz, 3H), 2.30-2.21(m, 1H), 2.10-2.01 (m, 1H), 1.92-1.82 (m, 1H) 257

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5H-pyrrolo[3,4- b]pyridine-6(7H)- carboxamide 402.3 E: 0.98 F: 1.15¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.43 (d, J = 4.6 Hz,1H), 8.24 (d, J = 7.7 Hz, 1H), 7.95-7.88 (m, 1H), 7.88-7.80 (m, 2H),7.75 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 7.6, 5.0 Hz, 1H), 6.57 (d, J =7.7 Hz, 1H), 4.57 (br d, J = 24.2 Hz, 4H), 4.14-4.05 (m, 1H), 3.88(quin, J = 8.5 Hz, 1H), 2.40-2.29 (m, 3H), 2.15 (br t, J = 9.6 Hz, 2H),1.98 (br t, J = 10.0 Hz, 1H) 258

5-methoxy-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)indoline-1- carboxamide 431.1 E: 1.56 F: 1.56¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.24 (d, J = 7.7 Hz,1H), 7.96-7.88 (m, 1H), 7.87-7.79 (m, 2H), 7.66 (d, J = 8.7 Hz, 1H),6.75 (s, 1H), 6.64-6.55 (m, 1H), 4.17-4.04 (m, 1H), 3.93-3.78 (m, 2H),3.64 (s, 2H), 3.04 (br t, J = 8.5 Hz, 2H), 2.57 (br s, 1H), 2.54 (s,3H), 2.38-2.26 (m, 3H), 2.15 (br t, J = 9.8 Hz, 2H), 1.98 (br t, J = 9.9Hz, 1H) 259

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)-6-(trifluoromethyl) indoline-1-carboxamide 469.2 E: 1.90 F: 1.90 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.08(s, 1H), 7.94-7.89 (m, 1H), 7.88-7.80 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H),7.15 (br d, J = 7.7 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.17-4.06 (m,1H), 3.93 (br t, J = 8.8 Hz, 2H), 3.88 (t, J = 8.5 Hz, 1H), 3.16 (br t,J = 8.5 Hz, 2H), 2.58 (br s, 1H), 2.40-2.28 (m, 3H), 2.22-2.11 (m, 2H),2.06-1.94 (m, 1H) 260

5-(N,N- dimethylsulfamoyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)indoline-1- carboxamide 508.1 E: 1.54 F: 1.53¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.24 (d, J = 7.8 Hz,1H), 7.94 (d, J = 8.5 Hz, 1H), 7.90 (br d, J = 7.3 Hz, 1H), 7.87-7.80(m, 2H), 7.49-7.42 (m, 2H), 6.97 (br d, J = 7.2 Hz, 1H), 4.17-4.07 (m,1H), 3.95 (br t, J = 8.9 Hz, 2H), 3.88 (quin, J = 8.5 Hz, 1H), 3.17 (brt, J = 8.7 Hz, 2H), 2.55 (br s, 1H), 2.54 (s, 7H), 2.40-2.27 (m, 3H),2.22-2.11 (m, 2H), 2.05-1.96 (m, 1H) 261

3-(morpholinomethyl)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)indoline-1- carboxamide 500.1 E: 1.16 F: 1.61¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.49 (s, 1H), 8.24 (d, J = 7.8 Hz,1H), 7.97-7.90 (m, 1H), 7.88-7.80 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H),7.18 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.83 (t, J = 7.4 Hz,1H), 6.79 (br d, J = 7.5 Hz, 1H), 4.17-4.07 (m, 1H), 4.00-3.92 (m, 1H),3.87 (quin, J = 8.4 Hz, 1H), 3.69-3.63 (m, 2H), 3.60 (br s, 1H),2.60-2.52 (m, 3H), 2.44-2.26 (m, 5H), 2.22-2.10 (m, 2H), 2.06-1.96 (m,1H) 262

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-2-(p-tolyl)-5H- pyrrolo[3,4- d]pyrimidine-6(7H)- carboxamide 493.2E: 1.71 F: 1.72 ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.82 (s,1H), 8.30-8.21 (m, 3H), 7.95-7.89 (m, 1H), 7.88-7.86 (m, 1H), 7.85- 7.79(m, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 7.7 Hz, 1H), 4.64 (br s,2H), 4.62 (br s, 2H), 4.17-4.05 (m, 1H), 3.89 (quin, J = 8.4 Hz, 1H),2.59 (br s, 1H), 2.37 (s, 3H), 2.35 (br d, J = 8.6 Hz, 3H), 2.17 (br t,J = 9.8 Hz, 2H), 2.00 (br t, J = 10.0 Hz, 1H) 263

5-methoxy-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)isoindoline-2- 431.2 E: 1.50 F: 1.50 ¹H NMR:(500 MHz, DMSO-d₆) δ ppm 12.48 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H),7.96-7.88 (m, 1H), 7.88-7.78 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 6.87 (s,1H), 6.84 (br d, J = 8.3 Hz, 1H), 6.45 (d, J = 7.7 Hz, 1H), 4.52 (br s,2H), 4.48 (br s, 2H), 4.14-4.03 (m, 1H), 3.87 (quin, J = 8.4 Hz, 1H),3.73 (s, 3H), 2.40- carboxamide 2.25 (m, 3H), 2.13 (br t, J = 9.5 Hz,2H), 1.96 (t, J = 10.0 Hz, 1H) 264

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-pyrrolo[3,4- 402.3 E: 0.87 F: 1.13 ¹H NMR: (500 MHz, DMSO-d₆) δppm 12.48 (s, 1H), 8.54 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.24 (d, J =7.8 Hz, 1H), 7.95-7.88 (m, 1H), 7.88-7.79 (m, 2H), 7.38 (d, J = 4.9 Hz,1H), 6.60-6.53 (m, 1H), 6.57 (br d, J = 7.6 Hz, 1H), c]pyridine-2(3H)-4.60 (br d, J = 8.2 Hz, 4H), 4.14-4.03 (m, 1H), carboxamide 3.87 (quin,J = 8.5 Hz, 1H), 2.39-2.28 (m, 3H), 2.19-2.11 (m, 2H), 1.97 (br t, J =10.0 Hz, 1H)

Example 265,N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2

tert-Butyl spiro[indoline-3,4′-piperidine]-1′-carboxylate (37 mg, 0.128mmol) was placed in a pressure vial, and a solution of Example 50A (21.6mg, 0.051 mmol) in THF (2 mL) was added, followed by DIEA (0.027 mL,0.15 mmol). The reaction mixture was stirred at it for 5 min, and thenat 50° C., for 16 h. The mixture was concentrated, then the residue wastreated with TFA (2 mL) at rt for 15 min. The mixture was concentratedand the residue was purified by preparative HPLC to afford Example 265(11.6 mg, 48% yield). MS(ESI) m/z: 470.3 (M+H)⁺; ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 12.49 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.96-7.90 (m, 1H),7.84 (dd, J=17.1, 8.2 Hz, 3H), 7.18-7.06 (m, 2H), 6.91 (t, J=7.4 Hz,1H), 6.72 (br d, J=7.4 Hz, 1H), 4.19-4.09 (m, 1H), 3.94-3.83 (m, 3H),3.36 (br d, J=11.7 Hz, 1H), 2.92 (br t, J=13.1 Hz, 2H), 2.63-2.56 (m,1H), 2.42-2.31 (m, 3H), 2.24-2.11 (m, 2H), 2.04-1.92 (m, 3H), 1.77 (brd, J=12.9 Hz, 2H); HPLC RT=1.18 min (Method E), 1.13 min (Method F).

Example 266,N,1-dimethyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide

Example 266A:N-((aR)-6-(3-(dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1-methyl-1H-indazole-3-carboxamide

To a solution of 1-methyl-1H-indazole-3-carboxylic acid (108 mg, 0.611mmol) was dissolved in anhydrous DMF (2.5 mL), then DIEA (0.291 mL, 1.66mmol) and HATU (243 mg, 0.638 mmol) were added. After stirring for 30min at rt, the obtained solution was added to a solution of Intermediate76 (194 mg, 0.555 mmol) and DIEA (0.291 mL, 1.66 mmol) in anhydrous DMF(2.5 mL), and the reaction mixture was stirred at rt for 1 h. Thereaction mixture was quenched with MeOH (0.5 mL), diluted with EtOAc(100 mL), washed with water (2×) and brine, dried (Na₂SO₄) andconcentrated. The residue was purified by flash chromatography (0-30%EtOAc/DCM gradient) to afford Example 266a (107 mg, 38% yield) as acolorless foam. MS(ESI) m/z: 508.4 (M+H)⁺; ¹H NMR: (500 MHz, CDCl₃) δppm 8.47 (dd, J=7.8, 1.0 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 7.81-7.76 (m,1H), 7.76-7.71 (m, 1H), 7.70-7.66 (m, 1H), 7.47-7.38 (m, 2H), 7.29 (ddd,J=8.0, 6.5, 1.1 Hz, 1H), 7.09 (br d, J=8.0 Hz, 1H), 4.61 (sxt, J=8.2 Hz,1H), 4.10 (s, 3H), 3.89 (quin, J=8.0 Hz, 1H), 3.82 (br t, J=9.2 Hz, 1H),2.83-2.76 (m, 1H), 2.66 (d, J=8.0 Hz, 2H), 2.61-2.55 (m, 1H), 2.55-2.45(m, 2H), 2.21 (dd, J=1.0, 8.8 Hz, 1H), 2.10-2.06 (m, 1H), 1.62-1.57 (m,1H), 0.74-0.67 (m, 2H), 0.56-0.49 (m, 2H), 0.40-0.32 (m, 4H).

Example 266

To a solution of Example 266A (15 mg, 0.030 mmol) in THF (1 mL) at 0°C., was added LiHMDS (1 M in THF) (0.044 mL, 0.044 mmol). The reactionmixture was stirred at 0° C., for 5 min, then methyl iodide (5.5 μl,0.089 mmol) was added. The reaction mixture was stirred at rt for 30min. Additional LiHMDS (1 M in THF) (0.044 mL, 0.044 mmol) was added,and the reaction mixture was stirred at 40° C., for 4 h. The solvent wasevaporated, and the residue was treated with TFA (2 mL) for 15 min atrt. The solvent was evaporated and the residue was purified bypreparative HPLC to afford Example 266 (5.2 mg, 39% yield). MS(ESI) m/z:428.3 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.48 (br s, 1H), 8.24(br d, J=7.4 Hz, 1H), 7.97-7.78 (m, 4H), 7.70 (d, J=8.5 Hz, 1H), 7.45(t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 4.98 (brs, 1H), 4.11 (s, 3H),3.89 (s, 1H), 2.54 (s, 3H), 2.46-2.31 (m, 4H), 2.24 (br t, J=10.1 Hz,1H); HPLC RT=1.64 min (Method E), 1.63 min (Method F).

Example 267:N-ethyl-1-methyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 266,substituting EtI for MeI afforded Example 267. MS(ESI) m/z: 442.1(M+H)⁺; ¹H NMR: (500 MHz. DMSO-d₆) δ ppm 12.46 (br s, 1H), 8.24 (br d,J=7.6 Hz, 1H), 7.98-7.78 (m, 4H), 7.69 (d, J=8.5 Hz, 1H), 7.45 (br t,J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 4.10 (s, 3H), 3.89 (br s, 1H),3.38 (br s, 2H), 2.54 (s, 3H), 2.43-2.27 (m, 4H), 2.21-2.10 (m, 2H),1.13 (br s, 3H); HPLC RT=1.96 min (Method E), 2.00 min (Method F).

Example 268.2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl2-aminoacetate, TFA

Example 268A.N-((aR)-6-(3-(dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide

Intermediate 29 (113 mg, 0.451 mmol) was dissolved in DMF (4.0 mL), thenDIEA (0.225 mL, 1.29 mmol) and HATU (171 mg, 0.451 mmol) were added.After stirring for 30 min at rt, the obtained solution was added to asolution of Intermediate 76 (150 mg, 0.429 mmol) and DIEA (0.225 mL,1.29 mmol) in DMF (4.0 mL), and the reaction mixture was stirred at rtfor 1 h. The reaction mixture was quenched with MeOH (0.5 mL), dilutedwith EtOAc (200 mL), washed with water (3×), brine (1×50 mL), dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (30-100% EtOAc/DCM gradient) to give Example 268A (215mg, 86% yield) as a white solid. MS(ESI) m/z: 582.6 (M+H)⁺; ¹H NMR: (500MHz, DMSO-d₆) δ ppm 8.45-8.41 (m, 2H), 8.28 (dd, J=8.0, 0.8 Hz, 1H),8.21 (d, J=7.7 Hz, 1H), 8.07 (d, J=9.1 Hz, 1H), 7.95-7.91 (m, 1H),7.89-7.81 (m, 2H), 7.27 (dd, J-=9.6, 2.2 Hz, 1H), 4.67 (s, 1H), 4.36(sxt, J=8.1 Hz, 1H), 3.97 (quin, J=8.0 Hz, 1H), 3.79 (s, 2H), 3.68 (brt, J=9.1 Hz, 1H), 2.66-2.56 (m, 2H), 2.48-2.45 (m, 2H), 2.45-2.38 (m,1H), 2.31-2.24 (m, 1H), 2.22-2.16 (m, 1H), 2.07 (dd, J=10.9, 9.2 Hz,1H), 1.52 (dt, J=7.6, 4.8 Hz, 2H), 1.22 (s, 6H), 0.66 (tt, J=8.6, 4.5Hz, 2H), 0.55 (dq, J=9.5, 4.9 Hz, 2H), 0.32 (qd, J=8.4, 4.1 Hz, 2H),0.17 (dq, J-=9.7, 4.7 Hz, 2H).

Example 268B:1-((3-(((aR)-6-(3-(dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)-2-methylpropan-2-yl2-((tert-butoxycarbonyl)amino)acetate

Example 268A (70 mg, 0.120 mmol) was dissolved in anhydrous DCM (5.0mL), then 2-((tert-butoxycarbonyl)amino)acetic acid (63 mg, 0.36 mmol)and 4-(pyrrolidin-1-yl)pyridine (17.8 mg, 0.120 mmol) were added. Thereaction mixture was heated to 35° C., and DIC (0.056 mL, 0.36 mmol) wasadded dropwise over 15 min. The reaction mixture was stirred foradditional 1 h at 35° C., then at it for additional 16 h. Additional2-((tert-butoxycarbonyl)amino)acetic acid (63 mg, 0.36 mmol) was added,followed by dropwise addition of DIC (0.056 mL, 0.36 mmol) over 15 minat 35° C. The reaction mixture was stirred at 35° C., for 1 h. Thereaction mixture was cooled to rt, quenched with MeOH (1 mL), andconcentrated. The residue was purified by preparative HPLC to affordExample 268B (50 mg, 56% yield) as a white solid. MS(ESI) m/z: 739.7(M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.55-8.49 (m, 1H), 8.45 (s,1H), 8.28 (d, J=8.0 Hz, 1H), 8.26-8.20 (m, 1H), 8.16-8.06 (m, 21-),7.96-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.32-7.26 (m, 1H), 7.12 (t, J=6.2Hz, 1H), 4.37 (sxt, J=8.1 Hz, 1H), 4.26-4.16 (m, 2H), 3.97 (quin, J=8.0Hz, 1H), 3.83-3.64 (m, 1H), 3.59 (d, J=6.1 Hz, 1H), 2.66-2.61 (m, 1H),2.61-2.54 (m, 1H), 2.45-2.38 (m, 1H), 2.31-2.24 (m, 1H), 2.22-2.15 (m,1H), 2.07 (t, J=10.0 Hz, 1H), 1.60-1.46 (m, 9H), 1.36 (s, 6H), 0.66 (tt,J=8.6, 4.6 Hz, 2H), 0.55 (dq, J=9.3, 4.8 Hz, 2H), 0.36-0.27 (m, 2H),0.17 (dq, J=9.4, 4.8 Hz, 2H).

Example 268

Example 268B (50 mg, 0.068 mmol) was dissolved in TFA (3 mL), and thereaction mixture was stirred for 30 min at rt. TFA was removed underreduced pressure, the residue was purified by preparative HPLC to affordExample 268 (20.9 mg, 47% yield) as a white solid. MS(ESI) m/z: 545.4(M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.53 (d, J=1.7Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.14 (br s, 3H), 8.11 (d,J=9.9 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.86-7.79 (m, 1H),7.28 (dd, J=9.6, 2.2 Hz, 1H), 4.37 (sxt, J=8.1 Hz, 1H), 4.24 (s, 2H),3.91 (t, J=8.5 Hz, 1H), 3.78 (br d, J=5.2 Hz, 2H), 2.67-2.60 (m, 1H),2.57 (ddd, J=10.9, 8.0, 3.0 Hz, 1H), 2.44-2.33 (m, 3H), 2.28-2.17 (m,2H), 2.04 (dd, J=11.0, 9.1 Hz, 1H), 1.58 (s, 6H); HPLC RT=5.18 min(Method A), 5.86 min (Method B).

Example 269.(S)-2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl2-amino-3-methylbutanoate, TFA

According to the procedure for the preparation of Example 268,substituting (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acidfor 2-((tert-butoxycarbonyl)amino)acetic acid afforded Example 269.MS(ESI) m/z: 587.6 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.46 (s,1H), 8.52 (d, J=1.7 Hz, 1H), 8.47 (s, 1H), 8.30-8.20 (m, 5H), 8.11 (d,J=9.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H),7.23 (dd, J=9.6, 2.2 Hz, 1H), 4.42-4.34 (m, 1H), 4.33 (d, J=10.5 Hz,1H), 4.21 (d, J=10.5 Hz, 1H), 3.95-3.88 (m, 1H), 3.88-3.83 (m, 1H),2.66-2.60 (m, 1H), 2.57 (ddd, J=10.9, 8.1, 3.0 Hz, 1H), 2.45-2.35 (m,3H), 2.28-2.17 (m, 2H), 2.17-2.09 (m, 1H), 2.04 (dd, J=11.0, 9.1 Hz,1H), 1.60 (s, 3H), 1.58 (s, 3H), 0.99 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.2Hz, 3H); HPLC RT=5.67 min (Method A), 6.43 min (Method B).

Example 270:(S)-2-methyl-1-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propan-2-yl2-aminopropanoate, TFA

According to the procedure for the preparation of Example 268,substituting (S)-2-((tert-butoxycarbonyl)amino)propanoic acid for2-((tert-butoxycarbonyl)amino)acetic acid afforded Example 270. MS(ESI)m/z: 559.5 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 12.47 (s, 1H), 8.52(d, J=2.2 Hz, 1H), 8.48 (s, 1H), 8.32-8.21 (m, 5H), 8.11 (d, J=9.6 Hz,1H), 7.95-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.31-7.21(m, 1H), 4.37 (dq, J=16.1, 8.2 Hz, 2H), 4.32-4.27 (m, 1H), 4.25-4.19 (m,1H), 3.90 (quin, J=8.5 Hz, 1H), 2.67-2.60 (m, 1H), 2.57 (ddd, J=11.0,8.1, 3.2 Hz, 1H), 2.45-2.33 (m, 3H), 2.28-2.17 (m, 2H), 2.08-2.00 (m,1H), 1.58 (s, 3H), 1.57 (s, 3H), 1.37 (d, J=7.2 Hz, 3H); HPLC RT=5.31min (Method A), 6.03 min (Method B).

Example 271:6-(2-hydroxy-2-methylpropoxy)-N-(6-(1-oxo-1,2-dihydroisoquinolin-4-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;TFA

Example 271A: 4-bromo-2-(dicyclopropylmethyl)isoquinolin-1(2H)-one

To a solution of Ph₃P (0.937 g, 3.57 mmol) in THF (8 mL) at 0° C., wasadded DIAD (0.694 mL, 3.57 mmol) dropwise. The reaction mixture wasstirred at 0° C., for 15 min (thick suspension formed). Then, asuspension of 4-bromoisoquinolin-1(2H)-one (0.400 g, 1.79 mmol) anddicyclopropylmethanol (0.263 mL, 2.23 mmol) in dry THF (8 mL) was added,and the reaction mixture was allowed to reach rt, and stirred at rt for16 h. An additional amount of Ph₃P (0.937 g, 3.57 mmol) was added, thereaction mixture was cooled to 0° C., and DIAD (0.694 mL, 3.57 mmol) wasadded dropwise. The reaction mixture was stirred for additional 2 h at0° C., and for 2 h at rt. The reaction mixture was quenched with MeOH (1mL), diluted with EtOAc (100 mL). Then CELITE® was added, the solventwas removed under reduced pressure and the residue was purified by flashchromatography (solid loading on CELITE®): (0-80% EtOAc/DCM gradient) togive Example 271A (0.191 g, 34% yield) as an off-white solid. MS(ESI)m/z: 317.9 (M+H)⁺; ¹H NMR: (400 MHz, CDCl₃) δ ppm 8.43 (dd, J=8.1, 0.7Hz, 1H), 7.85-7.81 (m, 1H), 7.74 (td, J=7.6, 1.3 Hz, 1H), 7.63 (s, 1H),7.58-7.52 (m, 1H), 3.99 (t, J=7.4 Hz, 1H), 1.21-1.15 (m, 2H), 0.79-0.69(m, 2H), 0.57 (dq, J=9.8, 4.9 Hz, 2H), 0.49-0.32 (m, 4H).

Example 271B:2-(dicyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one

A mixture of Example 271A (191 mg, 0.600 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (229 mg,0.900 mmol), and potassium acetate (177 mg, 1.80 mmol) in dioxane (4 mL)was degassed (3× vacuum/Ar). Then, PdCl₂(dppf) CH₂Cl₂ adduct (13 mg,0.018 mmol) was added, the reaction mixture was degassed again (3×vacuum/Ar), sealed in a vial and heated at 110° C., for 2 h. Thereaction mixture was cooled to rt, diluted with EtOAc, CELITE® was addedand the solvent was removed under reduced pressure. The residue waspurified by flash chromatography (solid loading on CELITE®, 0-50%EtOAc/hex gradient) to give Example 271B (196 mg, 89% yield) as a whitesolid. MS(ESI) m/z: 366.1 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 8.33(d, J=7.7 Hz, 1H), 8.23 (dd, J=8.1, 1.0 Hz, 1H), 7.90 (br s, 1H), 7.74(ddd, J=8.3, 7.0, 1.5 Hz, 1H), 7.50 (ddd, J=8.0, 7.1, 1.1 Hz, 1H),1.52-1.39 (m, 2H), 1.34 (s, 12H), 0.72-0.63 (m, 2H), 0.56 (dq, J=9.6,4.7 Hz, 2H), 0.40-0.31 (m, 2H), 0.14 (dq, J=9.8, 4.9 Hz, 2H).

Example 271C:(2-(dicyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)boronic acid

A mixture of Example 271B (196 mg, 0.537 mmol) and sodium periodate (344mg, 1.61 mmol), was stirred in THF (4 mL) and water (1 mL) for 30 min.Then, HCl (1M aq.) (0.376 mL, 0.376 mmol) was added, and the reactionmixture was stirred at rt for 6 h. The reaction mixture was filtered andwas purified by preparative HPLC to afford Example 271C (42 mg, 28%yield) as a white solid. MS(ESI) m/z: 284.0 (M+H)⁺; ¹H NMR: (500 MHz,DMSO-d₆) δ ppm 8.47 (d, J=8.3 Hz, 1H), 8.22 (dd, J=8.0, 1.1 Hz, 1H),8.15 (s, 2H), 7.66 (ddd, J=8.3, 7.0, 1.5 Hz, 1H), 7.48-7.40 (m, 1H),1.45 (br s, 2H), 0.72-0.62 (m, 2H), 0.56 (dq, J=9.3, 4.8 Hz, 2H),0.39-0.29 (m, 2H), 0.15 (dq, J=9.9, 4.8 Hz, 2H).

Example 271D, tert-butyl(6-(2-(dicyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)spiro[3.3]heptan-2-yl)carbamate

tert-Butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (100 mg, 0.44 mmol) and4-methoxybenzenesulfonohydrazide (90 mg, 0.44 mmol) were dissolved indioxane (2. mL), and MS 4A (100 mg) were added. The reaction mixturedegassed (3× vacuum/Ar), and then was stirred at 90° C., for 3 h underAr. The reaction mixture was cooled to rt, and Example 271C (42 mg,0.148 mmol), cesium carbonate (72.5 mg, 0.223 mmol) and MS 4A (100 mg)were added. The vial was degassed again (3× vacuum/Ar), and the reactionmixture was stirred at 110° C. under Ar for 18 h. Additional cesiumcarbonate (72.5 mg, 0.223 mmol) was added, along with water (0.1 mL),and the reaction mixture was stirred at 110° C., for 3 h. The reactionmixture was cooled to rt, degassed, capped, and stirred at 110° C., for14 h. The material was purified by preparative HPLC to afford Example271D (19 mg, 29% yield) as an off-white solid. MS(ESI) m/z: 449.4(M+H)⁺.

Example 271E.N-(6-(2-(dicyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)spiro[3.3]heptan-2-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide

Example 271D (19 mg, 0.042 mmol) was dissolved in TFA (1.0 mL), and thereaction mixture was stirred for 30 min. The solvent was evaporated toafford the amine salt. In a separate vial, Intermediate 29 (13.8 mg,0.055 mmol) was suspended in anhydrous DMF (1 mL), then DIEA (0.022 mL,0.13 mmol) and HATU (18.5 mg, 0.049 mmol) were added. After stirring for30 min at rt, the obtained solution was added to a solution of the aminesalt and DIEA (0.022 mL, 0.13 mmol) in anhydrous DMF (0.5 mL). Thereaction mixture was stirred at rt for 1 h, then was quenched with MeOH(0.1 mL), diluted with DMF and purified by preparative HPLC to affordExample 271E (10 mg, 41% yield). MS(ESI) m/z: 581.5 (M+H)⁺; ¹H NMR: (500MHz, THF-d₈) δ ppm 8.38-8.34 (m, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.21 (d,J=9.6 Hz, 1H), 8.13 (s, 1H), 7.64-7.57 (m, 2H), 7.41 (ddd, J=8.1, 6.5,1.7 Hz, 1H), 7.29 (br d, J=7.7 Hz, 1H), 7.23 (s, 1H), 7.15 (dd, J=9.6,2.2 Hz, 1H), 4.60-4.51 (m, 1H), 3.80 (s, 2H), 3.69-3.63 (m, 1H),2.71-2.65 (m, 4H), 2.52-2.44 (m, 1H), 2.39-2.31 (m, 1H), 2.26 (t, J=9.9Hz, 1H), 2.18 (dt, J=18.9, 9.7 Hz, 2H), 2.03 (t, J=10.0 Hz, 1H), 1.28(s, 6H), 0.71-0.64 (m, 2H), 0.57 (dq, J=9.3, 4.5 Hz, 2H), 0.40-0.28 (m,4H).

Example 271

Example 271E (10 mg, 0.017 mmol) was dissolved in TFA (2 mL) and wasstirred at rt for 30 min. The reaction mixture was transferred intomicrowave vial, capped and was irradiated at 80° C., for 15 min. TFA wasremoved under reduced pressure, and the residue was purified bypreparative HPLC to afford Example 271 (1.2 mg, 11% yield). MS(ESI) m/z:487.4 (M+H)⁺; ¹H NMR: (500 MHz, DMSO-d₆) δ ppm 10.19 (br s, 1H),8.34-8.30 (m, 1H), 8.27 (d, J=1.7 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 8.12(s, 1H), 7.64-7.60 (m, 1H), 7.60-7.56 (m, 1H), 7.40 (ddd, J=8.0, 6.7,1.5 Hz, 1H), 7.27 (br d, J=7.7 Hz, 1H), 7.15 (dd, J=9.6, 1.9 Hz, 1H),4.59-4.49 (m, 1H), 3.80 (s, 2H), 2.76-2.69 (m, 1H), 2.67-2.60 (m, 1H),2.45-2.38 (m, 1H), 2.35-2.28 (m, 1H), 2.18 (t, J=9.9 Hz, 2H), 2.11 (t,J=10.2 Hz, 1H), 2.01 (dd, J=11.0, 9.1 Hz, 1H), 1.28 (s, 6H); HPLCRT=6.81 min (Method A), 6.92 min (Method B).

Example 272, tert-butyl3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

To a suspension of6-Boc-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid (53.4mg, 0.189 mmol) and Intermediate 2, HCl (50 mg, 0.171 mmol) in DMF (1mL), were added HATU (71.7 mg, 0.189 mmol) and DIEA (0.090 mL, 0.51mmol). The resultant yellow solution was stirred at rt for 15 h. Themixture was partitioned between EtOAc and water. The aqueous phase wasextracted with EtOAc. The combined organic phase was washed with 1N HCland brine, dried (Na₂SO₄) and concentrated. The crude product waspurified by preparative HPLC to afford Example 272 (88 mg, 98% yield).MS(ESI) m/z: 521.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.48 (s, 1H),8.33 (d, J=7.5 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.96-7.89 (m, 1H),7.89-7.80 (m, 3H), 4.53 (br. s., 2H), 4.33-4.19 (m, 1H), 3.88 (quin,J=8.4 Hz, 1H), 3.53 (br, s., 1H), 2.78 (br, s., 2H), 2.63-2.56 (m, 1H),2.41-2.30 (m, 3H), 2.24-2.13 (m, 2H), 2.00 (t, J=10.0 Hz, 1H), 1.41 (s,9H); HPLC RT=1.88 min (Method E), 1.88 min (Method F).

Example 273,N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide,TFA

Example 272 (79 mg, 0.151 mmol) was dissolved in TFA (1 mL). The mixturewas stirred at it for 20 min, then was concentrated to afford the titlecompound (70 mg) as a white solid. MS(ESI) m/z: 421.2 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.27 (dd, J=19.2, 7.6 Hz, 2H),8.02-7.70 (m, 4H), 4.32-4.18 (m, 1H), 3.94-3.81 (m, 2H), 2.89 (d, J=5.4Hz, 2H), 2.72 (d, J=7.3 Hz, 2H), 2.61-2.55 (m, 1H), 2.43-2.27 (m, 3H),2.25-2.11 (m, 2H), 2.05-1.95 (m, 1H), 1.90 (br, s., 3H); HPLC RT=1.11min (Method E), 0.94 min (Method F).

Example 274.6-acetyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

To a solution of Example 273 (15 mg, 0.028 mmol) and TEA (20 μL, 0.14mmol) in THF (1 mL) at rt, was added Ac₂O (4 μL, 0.042 mmol). Themixture was stirred at rt 25 min, then was quenched with a drop of MeOH.The mixture was concentrated, then was purified by preparative HPLC toafford Example 274 (12.1 mg, 93% yield). MS(ESI) m/z: 463.0 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.32 (d, J=7.3 Hz, 1H), 8.25 (d,J=7.9 Hz, 1H), 7.95-7.79 (m, 4H), 4.31-4.20 (m, 1H), 3.88 (quin, J=8.3Hz, 1H), 3.68-3.59 (m, 2H), 3.39 (br, s., 2H), 2.91-2.84 (m, 2H), 2.75(br. s., 1H), 2.57 (d, J=11.3 Hz, 1H), 2.41-2.30 (m, 3H), 2.24-2.14 (m,2H), 2.11-2.03 (m, 3H), 2.03-1.96 (m, 1H); HPLC RT=1.42 min (Method E),1.46 min (Method F).

Example 275, methyl3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

To a solution of Example 273 (15 mg, 0.028 mmol) and TEA (20 μL, 0.143mmol) in THF (1 mL) at it, was added methyl chloroformate (3.26 μL,0.042 mmol). The heterogeneous mixture was stirred at rt for 25 min,then was quenched with a drop of MeOH. The mixture was concentrated,then was purified by preparative HPLC to afford Example 275 (13.0 mg,97% yield). MS(ESI) m/z: 479.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.46(s, 1H), 8.31 (d, J=7.3 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.97-7.80 (m,4H), 4.59 (br, s., 2H), 4.31-4.20 (m, 1H), 3.88 (quin, J=8.5 Hz, 1H),3.63 (s, 3H), 3.58 (t, J=5.8 Hz, 2H), 2.80 (br, s., 2H), 2.62-2.55 (m,1H), 2.41-2.29 (m, 3H), 2.24-2.13 (m, 2H), 2.04-1.96 (m, 1H); HPLCRT=1.61 min (Method E), 1.67 min (Method F).

Example 276.6-(methylsulfonyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

To a solution of Example 273 (15 mg, 0.028 mmol) and TEA (20 μL, 0.14mmol) in THF (1 mL) at rt, was added methanesulfonic anhydride (7.3 mg,0.42 mmol). The mixture was stirred at rt for 25 min, then was quenchedwith a drop of MeOH. The mixture was concentrated. The residue wasdissolved in 1:1 McOH/DMSO, filtered and submitted for purification,then was purified by preparative HPLC to afford Example 276. (3.2 mg,23% yield). MS(ESI) m/z: 499.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) 12.48(s, 1H), 8.36 (d, J=7.3 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.97-7.90 (m,2H), 7.90-7.82 (m, 2H), 4.44 (s, 2H), 4.28 (q, J=8.1 Hz, 1H), 3.91(quin, J=8.4 Hz, 1H), 2.96 (s, 3H), 2.94 (br, s., 2H), 2.65-2.58 (m,1H), 2.44-2.30 (m, 3H), 2.26-2.15 (m, 2H), 2.03 (t, J=10.1 Hz, 1H); HPLCRT=1.50 min (Method E), 1.49 min (Method F).

Example 277.6-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)benzo[e]isoxazole-3-carboxamide

A solution of Example 284 (10 mg, 0.021 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13mg, 0.063 mmol) in THF (2.0 mL) and Phosphoric acid, potassium salt (0.5M aq.) (0.083 mL, 0.042 mmol) was purged with argon. Pd-XPhos G3 (1.7mg, 2.0 μmol) was added. The pressure vial was capped, and the reactionmixture was stirred at 120° C., for 30 min. The mixture wasconcentrated, then was purified by preparative HPLC to afford Example277 (2.0 mg, 20% yield). MS(ESI) m/z: 481.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.50 (s, 1H), 9.44 (d, J=7.6 Hz, 1H), 8.37 (s, 1H), 8.27 (d,J=7.9 Hz, 1H), 8.10 (s, 1H), 7.99-7.77 (m, 5H), 7.57 (d, J=9.2 Hz, 1H),4.46-4.36 (m, 1H), 3.95-3.86 (m, 4H), 2.70-2.57 (m, 2H), 2.46-2.32 (m,4H), 2.30-2.23 (m, 1H), 2.22-2.15 (m, 1H); HPLC RT=1.72 min (Method E),1.76 min (Method F).

Example 278.1-(2-hydroxy-2-methylpropyl)-N-(6-(4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide,TFA

Example 278a. S-pyridin-2-yl6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carbothioate

6-(Boc-amino)spiro[3.3]heptane-2-carboxylic acid (197 mg, 0.733 mmol),triphenylphosphine (250 mg, 0.953 mmol), 2,2′-dipyridyl disulfide (210mg, 0.953 mmol) in degassed Toluene (5 mL) was stirred at RT for 3 days.The mixture was concentrated, and the residue purified by flashchromatography (0-70% EtOAc/hexanes gradient) to afford Example 278a(238 mg, 93% yield), as a pale yellow solid. MS(ESI) m/z: 349.2 (M+H)⁺;¹H NMR (400 MHz, chloroform-d) δ 8.65-8.59 (m, 1H), 7.77-7.70 (m, 1H),7.61 (dt, J=7.9, 0.9 Hz, 1H), 7.31-7.25 (m, 1H), 4.60 (br, s., 1H), 3.99(br, s., 1H), 3.39 (quin, J=8.4 Hz, 1H), 2.58-2.31 (m, 5H), 2.21 (ddd,J=11.8, 8.5, 3.5 Hz, 1H), 1.94-1.75 (m, 2H), 1.43 (s, 9H).

Example 278b, tert-butyl(6-(1H-pyrrole-2-carbonyl)spiro[3.3]heptan-2-yl)carbamate

To a solution of 1H-pyrrole (0.093 mL, 1.34 mmol) in THF (1 mL) at 0°C., was added dropwise methylmagnesium chloride (3M in THF) (0.35 mL,1.05 mmol). The mixture was stirred 15 mins, then was cooled to −78° C.To this mixture was added a solution of Example 278a (112 mg, 0.321mmol) in THF. The mixture was stirred at −78° C., for 10 mins, thengradually warmed up to 0° C., and stirred at that temperature for 1 hr.The mixture was quenched with conc, NH₄Cl, then was extracted withEtOAc. The organic phase washed with brine, dried (MgSO₄), andconcentrated. The residue purified by flash chromatography (0-75%EtOAc/hexanes gradient) to afford Example 278b (92 mg, 94% yield).MS(ESI) m/z: 305.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 9.44 (br s,1H), 7.02 (td, J=2.6, 1.3 Hz, 1H), 6.81 (ddd, J=3.7, 2.4, 1.3 Hz, 1H),6.26 (dt, J=3.7, 2.5 Hz, 1H), 4.62 (br, s., 1H), 4.02 (br, s., 1H), 3.69(quin, J=8.5 Hz, 1H), 2.66-2.52 (m, 1H), 2.49-2.24 (m, 4H), 2.21-2.09(m, 1H), 1.91 (dd, J=10.9, 8.7 Hz, 1H), 1.79 (dd, J=11.3, 8.7 Hz, 1H),1.44 (s, 9H).

Example 278c. (E)-tert-butyl(6-(hydrazono(1H-pyrrol-2-yl)methyl)spiro[3.3]heptan-2-yl)carbamate

Example 278b (75 mg, 0.25 mmol), hydrazine hydrate (0.5 mL, 10 mmol) ina sealed vial was heated at 90° C., for 4 hr, then was stirred at RT for3 days. The reaction mixture was diluted with DCM, then was washed withwater and brine, dried (MgSO₄) and concentrated to afford Example 278c(78 mg, 100% yield) as a light brown gum. The material was used in thefollowing step without further purification. MS(ESI) m/z: 319.3 (M+H)⁺.

Example 278d. (E)-methyl2-((6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)(2-(methoxycarbonyl)hydrazono)methyl)-1H-pyrrole-1-carboxylate

To a mixture of Example 278c (76 mg, 0.24 mmol) and pyridine (0.048 mL,0.60 mmol) in CH₂Cl₂ (2 mL) at 0° C., was added methyl carbonochloridate(0.037 mL, 0.48 mmol) dropwise. The mixture was stirred at 0° C., for 20min, then was partitioned between water and DCM. The organic phase waswashed with brine, dried (MgSO₄) and concentrated. The crude product waspurified by flash chromatography (0-90% EtOAc/hexanes gradient) toafford Example 278d (64 mg, 61% yield). MS(ESI) m/z; 435.3 (M+H)⁺.

Example 278c, tert-butyl(6-(4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

To Example 278d (64 mg, 0.147 mmol) in MeOH (2 mL), was added sodiummethoxide (25 wt % in MeOH) (159 mg, 0.737 mmol). The mixture was sealedand heated at 100° C., for 30 min. To the reaction mixture was added HCl(1.25N in MeOH) (0.589 mL, 0.737 mmol), then was purified by preparativeHPLC to afford Example 278e (32 mg, 63% yield), MS(ESI) m/z: 345.2(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 7.72 (dd, J=3.1, 1.3 Hz, 1H),6.79 (dd, J=3.6, 3.0 Hz, 1H), 6.75 (dd, J=3.7, 1.5 Hz, 1H), 4.01-3.87(m, 1H), 3.65 (quin, J=8.5 Hz, 1H), 2.64-2.55 (m, 1H), 2.55-2.23 (m,5H), 2.05 (dd, J=10.7, 8.9 Hz, 1H), 1.91 (dd, J=11.2, 8.8 Hz, 1H), 1.46(s, 9H).

Example 278f,1-(6-aminospiro[3.3]heptan-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one,HCl

Example 278e (32 mg, 0.093 mmol) in 4M HCl in Dioxane (1 mL) was stirredat rt for 2 h. The mixture was concentrated to afford Example 278f (25mg, 96% yield) as a grey solid. MS(ESI) m/z: 245.1 (M+H)⁺.

Example 278

To Example 278f (6 mg, 0.025 mmol),1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid (5.8 mg,0.025 mmol), HATU (14 mg, 0.037 mmol) in DMF (0.5 mL), was added DIEA(0.013 mL, 0.074 mmol). The mixture was sonicated to make a homogeneoussolution then was stirred at rt for 1 h. The product was purified bypreparative HPLC to afford Example 278 (8.5 mg, 58% yield). MS(ESI) m/z:461.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.23 (d, J=8.4 Hz, 1H),7.73 (dd, J=2.9, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.4,7.2, 1.0 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 6.82-6.79 (m, 1H), 6.79-6.76(m, 1H), 4.56-4.48 (m, 1H), 4.47 (s, 2H), 3.70 (quin, J=8.5 Hz, 1H),2.80-2.71 (m, 1H), 2.65-2.38 (m, 5H), 2.32 (dd, J=10.7, 8.9 Hz, 1H),2.18 (dd, J=11.2, 9.0 Hz, 1H), 1.27 (s, 6H); HPLC RT=8.25 min (MethodA), 7.26 min (Method B).

Example 279.6-(2-hydroxy-2-methylpropoxy)-N-(6-(4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide,TFA

According to the procedure for the preparation of Example 278,substituting Intermediate 29 for1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid affordedExample 279. MS(ESI) m/z: 477.3 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ8.36 (s, 1H), 8.29 (s, 1H), 8.13 (d, J=9.9 Hz, 1H), 7.71 (br, s., 1H),7.33 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 4.52-4.35 (m, 1H), 3.86(s, 2H), 3.75-3.60 (m, 1H), 2.71 (br, s., 1H), 2.63-2.33 (m, 5H), 2.25(t, J=9.6 Hz, 1H), 2.11 (t, J=10.0 Hz, 1H), 2.03 (br. s., 1H), 1.35 (s,6H); HPLC RT=6.92 min (Method A), 6.16 min (Method B).

Example 280.1-methyl-N-(6-(4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)-1H-indazole-3-carboxamide,TFA

According to the procedure for the preparation of Example 278,substituting 1-methyl-1H-indazole-3-carboxylic acid for1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid affordedExample 280. MS(ESI) m/z: 403.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ8.36 (s, 1H), 8.29 (s, 1H), 8.13 (d, J=9.9 Hz, 1H), 7.71 (br, s., 1H),7.33 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 4.52-4.35 (m, 1H), 3.86(s, 2H), 3.75-3.60 (m, 1H), 2.71 (br, s., 1H), 2.63-2.33 (m, 5H), 2.25(t, J=9.6 Hz, 1H), 2.11 (t, J=10.0 Hz, 1H), 2.03 (br, s., 1H), 1.35 (s,6H); HPLC RT=8.84 min (Method A), 7.76 min (Method B).

Example 281.6-(2-hydroxy-2-methylpropoxy)-N-(6-(8-methyl-4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide,TFA

Example 281a, tert-butyl(6-(3-methyl-1H-pyrrole-2-carbonyl)spiro[3.3]heptan-2-yl)carbamate andregioisomer

To a solution of 3-methyl-1H-pyrrole (52 mg, 0.45 mmol) in THF (0.5 mL)at 0° C., methylmagnesium chloride (3M in THF) (0.143 mL, 0.430 mmol)was added dropwise. After 15 min, the solution was cooled to −78° C.,and Example 278a (50 mg, 0.14 mmol) in 0.5 mL THF was added. The mixturewas stirred at −78° C., for 10 min, gradually warmed to 0° C., andstirred for 1 hr. The reaction was quenched with sat, NH₄Cl aq andextracted with EtOAc. The organic phase was washed with brine, dried(MgSO₄) and concentrated. The residue was purified by flashchromatography (0-60% EtOAc/hexanes gradient) to afford Example 281a (33mg, 72% yield) as an off-white solid. The product is a 2:5 mixture ofregioisomers. MS(ESI) m/z: 319.3 (M+H)⁺.

Example 281b. (E)-tert-butyl(6-(hydrazono(3-methyl-1H-pyrrol-2-yl)methyl)spiro[3.3]heptan-2-yl)carbamateand regioisomer

A mixture of Example 281a (32 mg, 0.10 mol) in hydrazine hydrate (0.3mL, 6.18 mmol) was sealed and heated at 90° C., for 6 h. The reactionmixture was partitioned between DCM and water. The DCM phase was washedwith brine, dried (MgSO₄) and concentrated to afford Example 281b (33mg). The product is a 2:5 mixture of regioisomers. MS(ESI) m/z: 333.2(M+H)⁺.

Example 281c, methyl(E)-2-((6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)(2-(methoxycarbonyl)hydrazono)methyl)-3-methyl-1H-pyrrole-1-carboxylate

To a solution of Example 281 b, pyridine (50 μl, 0.62 mmol) in CH₂Cl₂ (1mL) at 0° C., methyl carbonochloridate (30 μl, 0.388 mmol) was addeddropwise. The mixture was stirred for 15 min, then was diluted with DCM,washed with water and brine, dried (MgSO₄) and concentrated. The residuewas purified by flash chromatography (0-80% EtOAc/hexanes gradient) toafford Example 281c (40 mg, 90% yield) as a white solid. The product isa 2:5 mixture of regioisomers. MS(ESI) m/z: 449.3 (M+H)⁺.

Example 281d, tert-butyl(6-(8-methyl-4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4]triazin-1-yl)spiro[3.3]heptan-2-yl)carbamate

Example 281c (30 mg, 0.067 mmol) and sodium methanolate (25% wt in MeOH)(72.3 mg, 0.334 mmol) in MeOH (0.5 mL) was sealed and heated at 100° C.,for 30 mins. The mixture was treated with 0.4 mL 1.25N HCl in MeOH, thenwas purified by preparative HPLC to afford Example 28 Id (6 mg, 25%yield). MS(ESI) m/z: 359.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 7.59(d, J=3.1 Hz, 1H), 6.58 (d, J=3.1 Hz, 1H), 3.99-3.85 (m, 1H), 3.74(quin, J=8.1 Hz, 1H), 2.58-2.37 (m, 7H), 2.32-2.22 (m, 2H), 2.06-1.95(m, 1H), 1.88 (dd, J=11.2, 8.8 Hz, 1H), 1.42 (s, 9H).

Example 281e,1-(6-aminospiro[3.3]heptan-2-yl)-8-methylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one,HCl

Example 281d (6 mg, 0.017 mmol) in 4N HCl in Dioxane (0.2 mL, 0.800mmol) was stirred at rt for 30 min. The reaction mixture wasconcentrated to afford Example 281e (4.9 mg, 100% yield), which was usedas is in the following step. MS(ESI) m/z; 259.1 (M+H)⁺.

Example 281

Example 281e (5.0 mg, 0.017 mmol). Intermediate 29 (4.3 mg, 0.017 mmol),HATU (9.7 mg, 0.026 mmol), DIEA (8.9 μl, 0.051 mmol) in DMF was stirredat rt for 1 hr. The product was purified by preparative HPLC to affordExample 281 (2.5 mg, 24% yield). MS(ESI) m/z: 333.2 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.35 (s, 1H), 8.28 (d, J=1.5 Hz, 1H), 8.12 (d, J=9.7Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.32 (dd, J=9.7, 2.2 Hz, 1H), 6.60 (d,J=3.1 Hz, 1H), 4.49-4.35 (m, 1H), 3.86 (s, 2H), 3.83-3.74 (m, 1H),2.74-2.05 (m, 11H), 1.35 (s, 6H); HPLC RT=6.50 min (Method A), 7.60 min(Method B).

The following Examples in Table 19 were made by using the same procedureas shown in Example 1. Intermediate 2 was coupled with the appropriateacids. Various coupling reagents could be used other than the onedescribed in Example 1 such as HBTU, HATU, BOP, PyBop, EDC/HOBt.

TABLE 19 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 282

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-b] pyrimidine-3- carboxamide 401.2 E: 1.28 F: 1.34 ¹HNMR (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9 29 (d, J = 7.0 Hz, 1H), 8.83(d, J = 4.0 Hz, 1H), 8 56 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.96-7.77 (m, 3H), 7.27 (dd, J = 6.3, 4.4 Hz, 1H),4.47-4.34 (m, 1H), 3.97- 3.82 (m, 1H), 2.75-2.66 (m, 1H), 2.62- 2.57 (m,1H), 2.44-2.35 (m, 3H), 2.32 (d, J = 5.5 Hz, 1H), 2.18 (t, J = 9.6 Hz,1H), 2.00 (t, J = 9.9 Hz, 1H) 283

6-((3,5-dimethylphenyl) amino)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)imidazo[1,2-b]pyridazine-3- carboxamide 520.1 E: 1.47 F: 1.70 ¹H NMR (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 9.36 (s, 1H), 8.55 (d, J = 7.3 Hz, 1H), 8.26(d, J = 7.6 Hz, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.97-7.89 (m, 2H),7.88-7.79 (m, 2H), 7.11 (s, 2H), 7.01 (d, J = 9.5 Hz, 1H), 6.76 (s, 1H),4.32-4.20 (m, 1H), 3.93-3.80 (m, 1H), 2.36 (t, J = 9.8 Hz, 1H), 2.28 (s,8H), 2.20-2.13 (m, 1H), 1.81 (t, J = 9.6 Hz, 1H), 1.64 (t, J = 9.8 Hz,1H) 284

6-bromo-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzo[c]isoxazole-3- carboxamide 479.0 E: 1.86F: 1.87 ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.34-8.20 (m, 1H),8.09 (br s, 2H), 7.97-7.88 (m, 1H), 7.89-7.79 (m, 2H), 3.89 (t, J = 8 4Hz, 1H), 3.63-3.52 (m, 1H), 2.62-2.53 (m, 2H), 2.43-2.34 (m, 3H), 2.28(dd, J = 11.2, 8.6 Hz, 1H), 2.24-2.16 (m, 1H), 2.14-2.04 (m, 1H) 285

1-ethyl-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H- pyrazole-5- carboxamide 378.0 E: 1.43 F: 1.42 ¹H NMR (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.2 Hz,1H), 7.94-7.89 (m, 1H), 7.89- 7.80 (m, 2H), 7.79 (d, J = 1.2 Hz, 1H),6.59 (d, J = 1.2 Hz, 1H), 4.37-4.25 (m, 1H), 4.17 (q, J = 7.2 Hz. 2H),3.88 (quin, J = 8.4 Hz, 1H), 2.59-2.55 (m, 1H), 2.42-2.30 (m, 3H), 2.27(t, J = 9.9 Hz, 1H), 2.21-2.12 (m, 1H), 2.12- 2.05 (m, 1H), 1.39 (t, J =7.3 Hz, 3H) 286

1-(difluoromethyl)- N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)-1H- pyrazole-5- 400.0 E: 1.59 F: 1.61 ¹H NMR(500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.30 (d, J= 2.1 Hz, 1H), 8.25 (d, J = 7.9 Hz. 1H), 7.98-7.69 (m, 4H), 6.85 (d, J =2.1 Hz, 1H), 4.38-4.26 (m, 1H), 3.88 (quin, J = 8.3 Hz, 1H), 2.60-2.56(m, 1H), 2.43-2.26 (m, 4H), 2.22-2.04 (m, 2H) carboxamide 287

6-(2-hydroxy-2- methylpropoxy)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)benzo[c]isoxazole-3-carboxamide, TFA 489.2 E: 7.00 F: 8.05 ¹H NMR (400 MHz, methanol-d₄) δ8.45- 8.29 (m, 1H), 8.00-7.78 (m, 4H), 6.97 (dd, J = 9.5, 2.0 Hz, 1H),6.81 (d, J = 1.3 Hz, 1H), 4.55-4.41 (m, 1H), 3.96 (t, J = 8.4 Hz, 1H),3.91-3.83 (m, 2H), 2.79- 2.70 (m, 1H), 2.70-2.61 (m, 1H), 2.60- 2.53 (m,1H), 2.51-2.44 (m, 2H), 2.42- 2.29 (m, 2H), 2.19 (dd, J = 11.1, 9.1 Hz,1H), 1.40-1.31 (m, 6H)

The following Examples in Table 20 were prepared by using a similarprocedure as shown in Example 123 by reacting Intermediate 2 with theappropriate esters.

TABLE 20 HPLC LCMS Method, (M + RT Ex. R Name H)⁺ (min.) ¹H NMR 288

1-(3-chlorophenyl)-7-oxo- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- carboxamide 529.0 E: 1.78 F: 1.79 ¹H NMR (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.25 (d, J =7.9 Hz, 1H), 7.96 (br s, 1H), J = 7.93-7.88 (m, 1H), 7.88-7.80 (m, 2H),7.78 (s, 1H), 7.64 (d, J = 3.4 Hz, 1H), 7.55-7.50 (m, 2H), 4.40-4.30 (m,1H), 3.88 (quin, J = 8.4 Hz, 1H), 3.47-3.40 (m, 1H), 2.98 (t, J = 6.7Hz, 2H), 2.60-2.55 (m, 2H), 2.42-2.27 (m, 4H), 2.22-2.08 (m, 2H) 289

1-(4-methoxyphenyl)-7- oxo-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 4.5,6.7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- carboxamide 525.1 E: 1.64 F: 1.64 ¹H NMR (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.25 (d, J =7.6 Hz, 1H), 7.94-7.88 (m, 1H), 7.88-7.79 (m, 3H), 7.50 (d, J = 8.9 Hz,2H), 7.01 (d, J = 9.2 Hz, 2H), 4.40- 4.29 (m, 1H), 3.92-3.83 (m, 1H),3.82 (s, 3H), 3.42 (br s, 1H), 2.98 (t, J = 6.7 Hz, 2H), 2.54 (br. s.,2H), 2.42-2.27 (m, 4H), 2.21-2.08 (m, 2H) 290

5-chloro-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzo[d]isoxazole-3- carboxamide 435.3 E: 2.09F: 2.11 ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.36 (d, J = 7.6 Hz,1H), 8.27 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.98-7.81 (m, 4H), 7.78 (d,J = 8.9 Hz, 1H), 4.47-4.31 (m, 1H), 3.91 (t, J = 8.4 Hz, 1H), 2.72-2.57(m, 2H), 2.47- 2.32 (m, 4H), 2.26 (d, J = 5.2 Hz, 1H), 2.21-2.12 (m, 1H)291

6-acetamido-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzo[d]isoxazole-3- carboxamide 458.1 E: 1.64F: 1.67 ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 10.52 (s, 1H), 9.22(d, J = 7.6 Hz, 1H), 8.30-8.24 (m, 2H), 7.96- 7.90 (m, 2H), 7.89-7.81(m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 4.43-4.33 (m, 1H), 3.90 (t, J = 8.4Hz, 1H), 2.67-2.59 (m, 1H), 2.44-2.29 (m, 4H), 2.28-2.21 (m, 1H), 2.16(d, J = 9.5 Hz, 1H), 2.12 (s, 3H) 467

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5- a]pyrazine-3-carboxamide 401.2 E: 1.21 F: 1.07 ¹H NMR(500 MHz, DMSO-d₆) δ 12.50 (s, 1H), 9.55 (s, 1H), 8.86 (d, J = 4.3 Hz,1H), 8.67 (s, 1H), 8.62 (d, J = 6.9 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H),8.06 (d, J = 4.6 Hz, 1H), 7.98-7.77 (m, 3H), 4.46-4.31 (m, 1H), 3.91(quin, J = 8.5 Hz, 1H), 2.70-2.62 (m, J = 11.6 Hz, 1H), 2.61-2.56 (m,1H), 2.45- 2.32 (m, 3H), 2.30-2.19 (m, 2H), 2.07 (t, J = 10.0 Hz, 1H)468

5-bromo-N-((aR)-6-(4- oxo-3.4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)indoline-2- carboxamide, TFA 479.0 E: 1.91 F:1.97 ¹H NMR (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.26 (d, J = 7.6 Hz,1H), 8.07 (d, J = 7.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.88-7.79 (m, 2H),7.14 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 6.06(br s, 1H), 4.17 (td, J = 16.5, 7.9 Hz, 2H), 3.93-3.77 (m, 1H), 3.27(dd, J = 16.3, 10.5 Hz, 1H), 2.98-2.91 (m, 1H), 2.42-2.29 (m, 3H),2.21-2.06 (m, 2H), 1.99-1.89 (m, 2H) 470

7-morpholino-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2- a]pyridine-3- carboxamide, TFA485.1 E: 4.34 F: 6.61 ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.27(d, J = 7.9 Hz, 1H), 8.85 (d, J = 7.3 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J= 8.1 Hz, 1H), 7.97-7.78 (m, 3H), 7.38 (dd, J = 8.0, 2.5 Hz, 1H), 6.94(d, J = 2.4 Hz, 1H), 4.35 (sxt, J = 7.9 Hz, 1H), 3.91 (quin, J = 8.4 Hz,1H), 3.80- 3.66 (m, 4H), 3.55-3.42 (m, 4H), 2.72- 2.54 (m, 2H),2.44-2.36 (m, 3H), 2.33-2.18 (m, 2H), 2.11-2.00 (m, 1H)

The following Examples in Table 21 were made by using the same procedureas shown in Example 1. Intermediate 2 was coupled with the appropriateacids. Various coupling reagents could be used other than the onedescribed in Example 1, such as HBTU, HATU, BOP, PyBop, EDC/HOBt.

TABLE 21 HPLC LCMS Method, Ex. Structure Name [M + H]⁺ RT (min.) ¹H NMR(δ NMR) 292

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)imidazo[1,5-a]pyridine- 1-carboxamide 400.2 E: 1.32 F: 1.36 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.47-8.57 (m, 2H), 8.25 (d, J = 7.6 Hz, 1H),8.14 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.96- 7.78 (m, 3H),7.12-7.06 (m, 1H), 6.84 (t, J = 6.7 Hz, 1H), 4.47- 4.29 (m, 1H), 3.88(quin, J = 8.4 Hz, 1H), 2.57 (br. s., 2H), 2.43- 2.25 (m, 4H), 2.24-2.15(m, 1H), 2.14-2.06 (m, 1H) 293

5-methoxy-1-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 443.4 E: 1.73 F: 1.75(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.57 (d, J = 7.3 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.97-7.79 (m, 3H), 7.40 (d, J = 8.9 Hz, 1H), 7.08 (d, J =1.8 Hz, 1H), 7.00 (s, 1H), 6.90 (dd, J = 9.0, 2.3 Hz, 1H), 4.45- 4.25(m, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 1H), 3.76 (s, 3H), 2.66- 2.55 (m,2H), 2.44-2.32 (m, 3H), 2.30-2.16 (m, 2H), 2.13-2.01 (m, 1H) 294

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 413.2 E: 1.83 F:1.81 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 8.25(d, J = 7.6 Hz, 1H), 7.98-7.79 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.50(d, J = 8.5 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.13-7.08 (m, 2H), 4.41-4.27 (m, 1H), 3.96 (s, 3H), 3.90 (quin, J = 8.5 Hz, 1H), 2.66-2.56 (m,2H), 2.45-2.32 (m, 3H), 2.30-2.19 (m, 2H), 2.14-2.02 (m, 1H) 295

7-methoxy-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 429.4 E: 1.65 F:1.66 (500 MHz, DMSO-d₆) δ 12.44 (s, 1H), 11.22 (br s, 1H), 8.49 (d, J =7.3 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.95-7.71 (m, 3H), 7.14 (d, J =7.9 Hz, 1H), 7.00 (d, J = 1.5 Hz, 1H), 6.93 (t, J = 7.9 Hz, 1H), 6.70(d, J = 7.6 Hz, 1H), 4.40-4.23 (m, 1H), 3.88 (s, 3H), 3.87-3.81 (m, 1H),2.68-2.58 (m, 1H), 2.57-2.51 (m, 1H), 2.42-2.29 (m, 3H), 2.24 (br. s.,1H), 2.16 (t, J = 9.8 Hz, 1H), 2.03-1.94 (m, 1H) 296

5-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide 436.1 E: 1.07 F: 1.36 (500 MHz, DMSO-d₆) δ12.48 (s, 1H), 8.99 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H),7.96-7.90 (m, 1H), 7.90-7.80 (m, 2H), 4.38- 4.25 (m, 1H), 4.05-3.73 (m,3H), 3.04-2.84 (m, 3H), 2.61-2.54 (m, 6H), 2.45-2.27 (m, 4H), 2.19 (d, J= 8.2 Hz, 2H) 297

4-chloro-1-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heplan-2-yl)- 1H-indole-2-carboxamide 447.1 E: 1.98 F: 1.99(500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.81 (d, J = 7.6 Hz, 1H), 8.27 (d, J= 7.6 Hz, 1H), 8.00-7.81 (m, 3H), 7.54 (d, J = 8.2 Hz, 1H), 7.30- 7.26(m, 1H), 7.23 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 4.37 (sxt, J = 8.0 Hz,1H), 4.01 (s, 3H), 3.92 (quin, J = 8.5 Hz, 1H), 2.69-2.57 (m, 2H),2.48-2.34 (m, 3H), 2.33-2.21 (m, 2H), 2.12 (t, J = 9.9 Hz, 1H) 298

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-indole-2-carboxamide 399.1 E: 1.62 F: 1.61 (500 MHz, DMSO-d₆) δ 12.48(s, 1H), 11.47 (br s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.95-7.80 (m, 3H), 7.59 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.2Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.02 (t, J = 7.3 Hz,1H), 4.45-4.30 (m, 1H), 4.00-3.83 (m, 1H), 2.64 (br. s., 1H), 2.60-2.56(m, 1H), 2.45-2.33 (m, 3H), 2.25 (t, J = 9.6 Hz, 2H), 2.11-2.02 (m, 1H)299

2-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a]pyridine- 3-carboxamide 414.3E: 1.12 F: 1.37 (500 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.88 (d, J = 7.0 Hz,1H), 8.21 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.92-7.76 (m,3H), 7.51 (d, J = 8.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 6.96 (t, J =6.9 Hz, 1H), 4.41-4.27 (m, 1H), 3.86 (quin, J = 8.4 Hz, 1H), 2.61 (t, J= 11.3 Hz, 1H), 2.57-2.52 (m, 1H), 2.46 (br. s., 3H), 2.41-2.29 (m, 3H),2.27- 2.17 (m, 2H), 2.05 (t, J = 10.1 Hz, 1H) 300

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-indole-3-carboxamide 399.0 E: 1.48 F: 1.50 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 11.51 (br s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 7.6Hz, 1H), 8.02 (br. s., 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.95-7.80 (m, 3H),7.40 (d, J = 8.2 Hz, 1H), 7.16- 7.10 (m, 1H), 7.10-7.04 (m, 1H),4.47-4.31 (m, 1H), 3.90 (quin, J = 8.3 Hz, 1H), 2.66-2.56 (m, 2H),2.45-2.32 (m, 3H), 2.27-2.16 (m, 2H), 2.04 (t, J = 10.1 Hz, 1H) 301

7-chloro-1-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 446.9 E: 2.04 F: 2.06(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.98-7.77 (m, 3H), 7.60 (d, J = 7.9 Hz, 1H), 7.26 (d, J =7.3 Hz, 1H), 7.09-7.03 (m, 2H), 4.42-4.29 (m, 1H), 4.24 (s, 3H), 3.90(quin, J = 8.3 Hz, 1H), 2.63 (t, J = 11.6 Hz, 1H), 2.59-2.55 (m, 1H),2.44-2.32 (m, 3H), 2.30-2.19 (m, 2H), 2.08 (t, J = 9.9 Hz, 1H) 302

4-chloro-7-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 447.1 E: 1.97 F: 1.97(500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 11.72 (br s, 1H), 8.74 (d, J = 7.5Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.01-7.77 (m, 3H), 7.26 (s, 1H),7.07-7.01 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 4.52-4.32 (m, 1H), 3.93 (t,J = 8.4 Hz, 1H), 2,68 (br. s., 1H), 2.64-2.58 (m, 1H), 2.56 (s, 3H),2.47-2.36 (m, 3H), 2.29 (t, J = 9.5 Hz, 2H), 2.11 (t, J = 10.1 Hz, 1H)303

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)thieno[2,3-b]pyrazine-6- carboxamide 418.2 E: 1.45 F: 1.45 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 9.14 (d, J = 7.0 Hz, 1H), 8.82 (s, 1H), 8.70(s, 1H), 8.31 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.95- 7.80 (m, 3H),4.43-4.29 (m, 1H), 3.91 (quin, J = 8.4 Hz, 1H), 2.68 (br. s., 1H), 2.59(t, J = 7.9 Hz, 1H), 2.46-2.34 (m, 3H), 2.32-2.23 (m, 2H), 2.12 (t, J =10.1 Hz, 1H) 304

4-bromo-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)pyrazolo[1,5-a]pyridine- 3-carboxamide 477.9/479.9 A: 5.77 B: 7.27 (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.80 (dd, J =6.8, 0.7 Hz, 1H), 8.48 (d, J = 7.5 Hz, 1H), 8.29-8.23 (m, 1H), 8.21 (s,1H), 7.96-7.80 (m, 3H), 7.66 (dd, J = 7.5, 0.7 Hz, 1H), 6.91 (t, J = 7.2Hz, 1H), 4.32 (sxt, J = 8.1 Hz, 1H), 3.89 (quin, J = 8.4 Hz, 1H),2.68-2.53 (m, 2H), 2.43-2.31 (m, 3H), 2.29-2.15 (m, 2H), 2.02 (dd, J =11.0, 8.8 Hz, 1H) 305

6-chloro-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-benzo[d]imidazole-2- carboxamide 434.2 E:1.70 F: 1.73 (500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 9.20 (d, J = 8.0 Hz,1H), 8.26 (d, J = 7.2 Hz, 1H), 7.95-7.81 (m, 3H), 7.80-7.42 (m, 2H),7.32 (d, J = 8.0 Hz, 1H), 4.45-4.32 (m, 1H), 3.95-3.85 (m, 1H),2.66-2.55 (m, 2H), 2.43-2.33 (m, 4H), 2.21 (d, J = 8.5 Hz, 2H) 306

5-chloro-1-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 447.0 E: 2.00 F: 2.00(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.95-7.81 (m, 3H), 7.71 (s, 1H), 7.56 (d, J = 8.5 Hz,1H), 7.25 (d, J = 8.5 Hz, 1H), 7.08 (s, 1H), 4.42-4.29 (m, 1H), 3.96 (s,3H), 3.90 (t, J = 8.4 Hz, 1H), 2.62 (br. s., 1H), 2.56 (br. s., 1H),2.44-2.32 (m, 3H), 2.29-2.19 (m, 2H), 2.12-2.04 (m, 1H) 307

1-isopropyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-benzo[d]imidazole-5- carboxamide 442.2E: 1.21 F: 1.44 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.09 (br s, 1H),8.73 (d, J = 7.0 Hz, 1H), 8.34-8.20 (m, 2H), 7.98-7.81 (m, 5H),4.99-4.82 (m, 1H), 4.46-4.28 (m, 1H), 3.91 (t, J = 8.2 Hz, 1H),2.70-2.56 (m, 2H), 2.45-2.33 (m, 3H), 2.32-2.20 (m, 2H), 2.14-2.04 (m,1H), 1.59 (d, J = 6.7 Hz, 6H) 308

N-((aR)-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-benzo[d]imidazole-5- carboxamide 400.2 E: 1.09 F: 1.19 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.57 (d, J = 7.3 Hz, 1H), 8.37 (s, 1H), 8.26(d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 7.95-7.80 (m, 3H), 7.75 (d, J = 8.5Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 4.47-4.29 (m, 1H), 3.90 (quin, J =8.5 Hz, 1H), 2.69-2.56 (m, 2H), 2.44-2.32 (m, 3H), 2.30-2.17 (m, 2H),2.09 (t, J = 9.9 Hz, 1H) 309

2-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-benzo[d]imidazole-5- carboxamide 414.2E: 1.11 F: 1.22 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.52 (d, J = 7.3 Hz,1H), 8.25 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 7.95-7.80 (m, 3H), 7.68 (d,J = 8.5 Hz, 1H), 7 47 (d, J = 8.5 Hz, 1H), 4.44-4.29 (m, 1H), 3.90(quin, J = 8.4 Hz, 1H), 2.65-2.56 (m, 2H), 2.52 (s, 3H), 2.44-2.33 (m,3H), 2.30-2.19 (m, 2H), 2.15-2.03 (m, 1H) 310

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3H-imidazo[4,5- b]pyridine-6-carboxamide 400.9 E: 1.07 F: 1.11 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.86 (s, 1H), 8.75 (d, J = 7.0 Hz, 1H), 8.59(s, 1H), 8.47 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.96- 7.79 (m, 3H),4.44-4.33 (m, 1H), 3.91 (t, J = 8.5 Hz, 1H), 2.70-2.56 (m, 2H),2.45-2.32 (m, 3H), 2.31-2.20 (m, 2H), 2.15-2.03 (m, 1H) 311

4-formamido-3-hydroxy-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 418.9 E: 1.23 F: 1.21 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 9.72 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.31(s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.94-7.80(m, 3H), 7.35 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 4.41- 4.22 (m, 1H),3.89 (t, J = 8.5 Hz, 1H), 2.57 (br. s., 2H), 2.42-2.33 (m, 3H),2.25-2.17 (m, 2H), 2.10-2.00 (m, 1H) 312

N-((aR)-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-b]pyridine- 2-carboxamide 399.9 E: 1.18 F: 1.40 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 11.99 (br. s., 1H), 8.62 (d, J = 7.5 Hz, 1H),8.31 (d, J = 4.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 7.9 Hz,1H), 7 96-7.80 (m, 3H), 7.16-7.05 (m, 2H), 4.44- 4.29 (m, 1H), 3.91(quin, J = 8.4 Hz, 1H), 2.66 (br. s., 1H), 2.57 (d, J = 11.0 Hz, 1H),2.45-2.33 (m, 3H), 2.30-2.20 (m, 2H), 2.11-2.04 (m, 1H) 313

6-chloro-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzo[b]thiophene-2- carboxamide 450.1 E: 1.99F: 1.99 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.93 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7 97-7.79 (m, 4H),7.46 (d, J = 8.5 Hz, 1H), 4.38-4.25 (m, 1H), 3.90 (quin, J = 8.4 Hz,1H), 2.70-2.60 (m, 1H), 2.57 (br. s., 1H), 2.44-2.33 (m, 3H), 2.26 (t, J= 9.6 Hz, 2H), 2.14-2.04 (m, 1H) 314

6-methoxy-1-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 443.0 E: 1.79 F: 1.79(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.25 (d, J= 7.6 Hz, 1H), 7.97-7.79 (m, 3H), 7.49 (d, J = 8.9 Hz, 1H), 7.05 (s,1H), 6.99 (s, 1H), 6.73 (d, J = 8.5 Hz, 1H), 4.40-4 26 (m, 1H), 3.93 (s,3H), 3.89 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 2.65-2.55 (m, 2H),2.44-2.34 (m, 3H), 2.29-2.20 (m, 2H), 2.07 (t, J = 9.9 Hz, 1H) 315

2-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzo[d]oxazole-6- carboxamide 415.2 E: 1.43F: 1.43 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.66 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.9 Hz, 1H), 8.11 (s, 1H), 7.96-7.79 (m, 4H), 7.70 (d, J =8.2 Hz, 1H), 4.46-4.30 (m, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.64 (s,4H), 2.57 (br. s., 1H), 2.43-2.34 (m, 3H), 2.30-2.21 (m, 2H), 2.13- 2.05(m, 1H) 316

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-1H-indazole-6- carboxamide 399.9 E: 1.33 F: 1.33 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.70 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.13(s, 1H), 8.04 (s, 1H), 7.95-7.77 (m, 4H), 7.58 (d, J = 8.5 Hz, 1H),4.50-4.27 (m, 1H), 3.91 (t, J = 8.4 Hz, 1H), 2.70-2.56 (m, 2H),2.44-2.33 (m, 3H), 2.31-2.20 (m, 2H), 2.15- 2.04 (m, 1H) 317

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-benzo[d]imidazole-5- carboxamide 414.0E: 1.11 F: 1.28 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.57 (d, J = 7.3 Hz,1H), 8.30- 8.17 (m, 3H), 7.95-7.76 (m, 4H), 7.61 (d, J = 8.5 Hz, 1H),4.47- 4.32 (m, 1H), 3.95-3.87 (m, 1H), 3.86 (s, 3H), 2.67-2.55 (m, 2H),2.45-2.33 (m, 3H), 2.31-2.19 (m, 2H), 2.13-2.05 (m, 1H) 318

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine- 3-carboxamide 400.0 E: 1.12 F: 1.38 (500 MHz,DMSO-d₆) δ 12.48 (s, 1H), 9.54 (d, J = 7.0 Hz, 1H), 8.85 (d, J = 7.0 Hz,1H), 8.5 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.96-7.89 (m, 1H), 7.89-7.79(m, 3H), 7.74 (t, J = 7.9 Hz, 1H), 7.18-7.11 (m, 1H), 4.45-4.31 (m, 1H),3.90 (t, J = 8.4 Hz, 1H), 2.66 (br. s., 1H), 2.58 (br. s., 1H),2.45-2.32 (m, 3H), 2.31-2.19 (m, 2H), 2.07 (t, J = 10.1 Hz, 1H) 319

5-(benzyloxy)-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 505.0 E: 1.99 F: 1.99(500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 11.31 (s, 1H), 8.54 (d, J = 7.6 Hz,1H), 8.25 (d, J = 7.9 Hz, 1H), 7.96-7.79 (m, 3H), 7.45 (d, J = 7.6 Hz,2H), 7.38 (t, J = 7.5 Hz, 2H), 7,34-7.27 (m, 2H), 7.15 (s, 1H), 7.03 (s,1H), 6.90 (d, J = 8.5 Hz, 1H), 5.07 (s, 2H), 4.43- 4.27 (m, 1H),3.99-3.81 (m, 1H), 2.63 (br. s., 1H), 2.56 (br. s., 1H), 2.43-2.33 (m,3H), 2.29-2.19 (m, 2H), 2.06 (t, J = 9.8 Hz, 1H) 320

6-fluoro-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 416.9 E: 1.70 F: 1.77(500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 11.54 (br. s., 1H), 8.61 (d, J = 7.6Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.88- 7.79 (m,2H), 7.66-7.57 (m, 1H), 7.15 (br. s., 2H), 6.90 (t, J = 9.0 Hz, 1H),4.42-4.26 (m, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.63 (br. s., 1H), 2.56(br. s., 1H), 2.43-2.33 (m, 3H), 2.23 (t, J = 9.3 Hz, 2H), 2.06 (t, J =9.6 Hz, 1H) 321

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-2,3-dihydro-1H-indene-1- carboxamide 400.2 E: 1.62 F: 1.68 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.39 (d, J = 7.0 Hz, 1H), 8.24 (d, J = 7.6 Hz,1H), 7.95-7.88 (m, 1H), 7.87-7.79 (m, 2H), 7.24- 7.06 (m, 4H), 4.20-4.04(m, 1H), 3.86 (quin, J = 8.3 Hz, 1H), 3.79 (t, J = 7.5 Hz, 1H),3.02-2.91 (m, 1H), 2.80 (dt, J = 15.7, 8.0 Hz, 1H), 2.61-2.51 (m, 2H),2.41-2.28 (m, 3H), 2.25-2.03 (m, 4H), 1.91 (q, J = 10.1 Hz, 1H) 322

7-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 413.4 E: 1.74 F:1.78 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 11.26 (br. s., 1H), 8.57 (d, J= 7.6 Hz, 1H), 8.28 (d, J = 7 6 Hz, 1H), 7.99-7.81 (m, 3H), 7.44 (d, J =7.6 Hz, 1H), 7.14 (s, 1H), 7.02-6.91 (m, 2H), 4.47-4.33 (m, 1H), 3.93(quin, J = 8.5 Hz, 1H), 2.67 (d, J = 11.9 Hz, 1H), 2.63-2.58 (m, 1H),2.56 (s, 3H), 2.47-2.36 (m, 3H), 2.33-2.23 (m, 2H), 2.10 (t, J = 9.8 Hz,1H) 323

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)isoindoline-1- carboxamide 401.0 E: 1.24 F: 1.45 (500 MHz, DMSO-d₆) δ12.47 (s, 1H) 9.20 (d, J = 7.0 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H),7.95-7.88 (m, 1H), 7.87-7.79 (m, 2H), 7.52 (br. s., 1H), 7.44 (s, 3H),5.35 (s, 1H), 4.70-4.51 (m, 2H), 4.21-4.06 (m, 1H), 3.93-3.81 (m, 1H),2.58 (d, J = 11.6 Hz, 2H), 2.43-2.34 (m, 3H), 2.28 (br. s., 1H), 2.11(t, J = 9.6 Hz, 1H), 2.06-1.98 (m, 1H) 325

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine- 2-carboxamide 399.4 E: 1.53 F: 1.54 (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.66 (d, J = 7.0 Hz, 1H), 8.58 (d, J =7.9 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95-7.81 (m, 3H), 7.76 (d, J =8.9 Hz, 1H), 7.33-7.23 (m, 1H), 7.02 (t, J = 6.3 Hz, 1H), 6.97 (s, 1H),4.45-4.30 (m, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 2.64-2.55 (m, 2H),2.45-2.27 (m, 4H), 2.24-2.17 (m, 1H), 2.16-2.10 (m, 1H) 326

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)isoquinoline-3- carboxamide 411.4 E: 1.59 F: 1.78 (500 MHz, DMSO-d₆)δ 12.47 (s, 1H), 9.37 (s, 1H), 9.00 (d, J = 8.2 Hz, 1H), 8.52 (s, 1H),8.25 (t, J = 6.9 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 7.96-7.75 (m, 5H),4.45 (sxt, J = 8.2 Hz, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 2.67-2.55 (m,2H), 2.45-2.30 (m, 4H), 2.28-2.12 (m, 2H) 327

7-hydroxy-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 415.1 E: 1.38 F:1.40 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 11.04 (br. s., 1H), 8.59 (d, J= 7.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.01-7.74 (m, 3H), 7.11- 6.97(m, 2H), 6.85 (t, J = 7.7 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 4.46- 4.25(m, 1H), 3.91 (t, J = 8.4 Hz, 1H), 2.71-2.56 (m, 2H), 2.45-2.33 (m, 3H),2.30-2.19 (m, 2H), 2.05 (t, J = 9.9 Hz, 1H) 328

7-chloro-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxaniide 433.0 E: 1.73 F:1.74 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 11.58 (br. s., 1H), 8.69 (d, J= 7.2 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.98-7.79 (m, 3H), 7.61 (d, J =7.9 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.19 (s, 1H), 7.06 (t, J = 7.7Hz, 1H), 4.43-4.31 (m, 1H), 3.98-3.84 (m, 1H), 2.73-2.56 (m, 2H),2.44-2.33 (m, 3H), 2.31-2.17 (m, 2H), 2.07 (t, J = 10.1 Hz, 1H) 329

6-fluoro-7-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indoie-2-carboxamide 431.1 E: 1.72 F: 1.75(500 MHz, DMSO-d₆) δ 12.50 (s, 1H), 11.48 (br. s., 1H), 8.57 (d, J = 7.5Hz, 1H), 8.27 (d, J = 7.7 Hz, 1H), 7.98-7.77 (m, 1H), 7.45 (dd, J = 8.3,5.2 Hz, 1H), 7.15 (s, 1H), 6.89 (t, J = 9.5 Hz, 1H), 4.46- 4.29 (m, 1H),3.98-3.82 (m, 1H), 2.66 (br. s., 1H), 2.62-2.56 (m, 1H), 2.42 (s, 3H),2.46-2.33 (m, 3H), 2.31-2.20 (m, 2H), 2.08 (t, J = 9.9 Hz, 1H) 330

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)quinoline-2- carboxamide 411.1 E: 1.78 F: 1.86 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 9.02 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 8.2 Hz, 1H), 8.26(d, J = 7.9 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H),8.08 (d, J = 8.2 Hz, 1H), 7.96-7.80 (m, 4H), 7.72 (t, J = 7.2 Hz, 1H),4.44 (sxt, J = 8.1 Hz, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.70-2.56 (m,2H), 2.46-2.34 (m, 4H), 2.30-2.20 (m, 2H) 331

4-bromo-N-((aR)-6-(4-oxo- 3.4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 438.0/ 440.0 E: 1.70 F: 1.77 (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.67 (d, J = 7.3 Hz, 1H), 8.25 (d, J =7.9 Hz, 1H), 7.94-7.88 (m, 1H), 7.88-7.81 (m, 2H), 7.79 (d, J = 8.2 Hz,2H), 7.66 (d, J = 8.5 Hz, 2H), 4.32 (sxt, J = 7.9 Hz, 1H), 3.89 (quin, J= 8.4 Hz, 1H), 2.65-2.55 (m, 2H), 2.44-2.29 (m, 3H), 2.28-2.15 (m, 2H),2.05 (t, J = 10.1 Hz, 1H) 332

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-7-(trifluoromethyl)-1H- indole-2-carboxamide 467.0 E: 1.84 F: 1.84 (500MHz, DMSO-d₆) δ 12.50 (s, 1H), 11 34 (br. s., 1H), 8.83 (d, J = 7.1 Hz,1H), 8.25 (d, J = 7.9 Hz, 1H), 8.03-7.79 (m, 4H), 7.58 (d, J = 7.3 Hz,1H), 7.33-7.16 (m, 2H), 4.44-4.27 (m, 1H), 3.91 (t, J = 8.2 Hz, 1H),2.68 (br. s., 1H), 2.58 (d, J = 7.6 Hz, 1H), 2.45-2.33 (m, 3H),2.32-2.20 (m, 2H), 2.07 (t, J = 10.0 Hz, 1H) 333

7-fluoro-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 417.1 E: 1.61 F: 1.62(500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 11.95 (br. s., 1H), 8.64 (d, J = 7.4Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.00-7.75 (m, 3H), 7.43 (br. s., 1H),7.19 (br. s., 1H), 7.04-6.91 (m, 2H), 4.44-4.28 (m, 1H), 3.97-3.83 (m,1H), 2.70-2.55 (m, 2H), 2.44-2.32 (m, 3H), 2.31- 2.16 (m, 2H), 2.06 (t,J = 9.9 Hz, 1H) 334

4,7-dimethoxy-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 459.4 E: 1.66 F: 1.72(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 11.29 (s, 1H), 8.49 (d, J = 7.3 Hz,1H), 8.25 (d, J = 7.6 Hz, 1H), 7.96-7.80 (m, 3H), 7.09 (d, J = 2.1 Hz,1H), 6.61 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 8.2 Hz, 1H), 4.40-4.27 (m,1H), 3.90 (t, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.70-2.61 (m,1H), 2.60-2.55 (m, 1H), 2.45-2.33 (m, 3H), 2.31-2.23 (m, 1H), 2.20 (t, J= 9.8 Hz, 1H), 2.05-1.98 (m, 1H) 335

5-fluoro-7- (methylsulfonyl)-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 495.0 E: 1.58 F: 1.65(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 10.76 (s, 1H), 9.00 (d, J = 7.3 Hz,1H), 8.25 (d, J = 7.6 Hz, 1H), 7.97-7.80 (m, 4H), 7.62 (dd, J = 8.7, 2.3Hz, 1H), 7.34 (s, 1H), 4.45-4.29 (m, 1H), 3.91 (quin, J = 8.5 Hz, 1H),2.71-2.63 (m, 1H), 2.62-2.56 (m, 1H), 2.54 (s, 3H), 2.45-2.34 (m, 3H),2.31-2.21 (m, 2H), 2.13-2.04 (m, 1H) 336

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3-(1H-pyrazol-1- yl)benzamide 426.1 E: 1.49 F: 1.54 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.64 (d, J = 7.3 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.25(d, J = 7.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.94- 7.80 (m, 5H), 7.79 (s,1H), 6.58 (s, 1H), 4.41-4.30 (m, 1H), 3.95- 3.84 (m, 1H), 2.66-2.55 (m,2H), 2.44-2.31 (m, 3H), 2.29-2.19 (m, 2H), 2.12-2.03 (m, 1H) 337

N-((aR)-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-4-(1H-pyrazol-4- yl)benzamide 426.1 E: 1.29 F: 1.34 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8 53 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.03(br. s., 2H), 7.94-7.78 (m, 5H), 7.68 (d, J = 8.2 Hz, 2H), 4 41-4.29 (m,1H), 3.99-3.79 (m, 1H), 2.66-2.56 (m, 2H), 2.44-2.31 (m, 3H), 2 28-2.18(m, 2H), 2.07 (t, J = 9.9 Hz, 1H) 338

3-(2-morpholinoethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 489.2 E: 1.17 F: 1.46 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.6 Hz,1H), 7.97-7.80 (m, 3H), 7.46-7.38 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H),7.08 (d, J = 7.9 Hz, 1H), 4.41-4.27 (m, 1H), 4.15 (br. s., 2H), 3.90(quin, J = 8.4 Hz, 1H), 3.59 (br. s., 2H), 3.41-2.66 (m, 8H), 2.64-2.56(m, 2H), 2.43-2.31 (m, 3H), 2.29-2.17 (m, 2H), 2.11-2.02 (m, 1H) 339

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3-(1H-pyrazol-4- yl)benzamide 426.1 E: 1.32 F: 1.37 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.57 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.11(s, 2H), 8.03 (s, 1H), 7 96-7.79 (m, 3H), 7.74 (d, J = 7.6 Hz, 1H), 7.64(d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 4.43-4.30 (m, 1H), 3.91(quin, J = 8.3 Hz, 1H), 2.69-2.55 (m, 2H), 2.44-2.33 (m, 3H), 2.29-2.20(m, 2H), 2.13-2.03 (m, 1H) 340

3-(4-methylthiazol-2-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 457.1 E: 1.64 F: 1.76 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.80 (d, J = 7.3 Hz, 1H), 8.34 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.96-7.79 (m, 4H), 7.57(t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 4.44-4.31 (m, 1H), 3.90 (quin, J =8.4 Hz, 1H), 2.68-2.56 (m, 2H), 2.45 (s, 3H), 2.43- 2.33 (m, 3H),2.31-2.20 (m, 2H), 2.11 (t, J = 10.1 Hz, 1H) 341

6-methoxy-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)nicotinamide 391.2 E: 1.35 F: 1.43 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 7.3 Hz,1H), 8.25 (d, J = 7.9 Hz, 1H), 8.11 (dd, J = 8.7, 2.3 Hz, 1H), 7.95-7.79(m, 3H), 6.87 (d, J = 8.5 Hz, 1H), 4.39-4.27 (m, 1H), 3.96-3.82 (m, 4H),2.66-2.55 (m, 2H), 2.44-2.30 (m, 3H), 2.22 (t, J = 9.6 Hz, 2H),2.09-1.99 (m, 1H) 342

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(trifluoromethyl)nicotinamide 429.1 E: 1.56 F: 1.62 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 9.13 (s, 1H), 9.01 (d, J = 7.0 Hz, 1H), 8.45 (d, J = 7.9Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95-7.80(m, 3H), 4.36 (sxt, J = 8.0 Hz, 1H), 3.90 (quin, J = 8.5 Hz, 1H),2.71-2.61 (m, 1H), 2.60-2.55 (m, 1H), 2.45- 2.32 (m, 3H), 2.31-2.21 (m,2H), 2.08 (t, J = 9.9 Hz, 1H) 343

2-hydroxy-6-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)nicotinamide 391.2 E: 1.18 F: 1.23 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 9.89 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.9 Hz,1H), 8.18 (d, J = 7.6 Hz, 1H), 7.95-7.78 (m, 3H), 6.29 (d, J = 7.3 Hz,1H), 4.38-4.17 (m, 1H), 3.89 (quin, J = 8.4 Hz, 1H), 2.71-2.61 (m, 1H),2.57 (br. s., 1H), 2.43-2.32 (m, 3H), 2.28 (s, 3H), 2.31-2.26 (m, 1H),2.12-2.04 (m, 1H), 1.93-1.84 (m, 1H) 344

N-((aR)-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(2-(pyrrolidin-1- yl)ethyl)nicotinamide 458.2 E: 1.08 F: 1.12 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.95 (s, 1H), 8.78 (d, J = 7.0 Hz, 1H), 8 25(d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.95-7.75 (m, 3H), 7.46(d, J = 7.9 Hz, 1H), 4.44-4.26 (m, 1H), 3.90 (t, J = 8.4 Hz, 1H), 3.57(br. s., 2H), 3.23 (t, J = 7.3 Hz, 2H), 2,68-2.55 (m, 2H), 2.44-2.32 (m,3H), 2.24 (t, J = 9.5 Hz, 2H), 2.07 (t, J = 9.9 Hz, 1H), 2.03-1.77 (m,4H). 345

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-4-(2H-tetrazol-5- yl)benzamide 427.9 E: 1.29 F: 1.09 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.76 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H),8.14-8.06 (m, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.95- 7.89 (m, 1H),7.88-7.80 (m, 2H), 4.43-4.25 (m, 1H), 3.90 (quin, J = 8.5 Hz, 1H),2.68-2.61 (m, 1H), 2.60-2.55 (m, 1H), 2.44-2.33 (m, 3H), 2.29-2.20 (m,2H), 2.12-2.04 (m, 1H) 346

N-((aR)-6-(4-oxo-3.4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(1H-pyrazol-1- yl)nicotinamide 427.2 E: 1.53 F: 1.53 (500 MHz, DMSO-d₆)δ 12.47 (s, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 7.3 Hz, 1H),8.66 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.5, 2.1 Hz, 1H), 8.25 (d, J =7.9 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.94-7.89 (m, 1H), 7.89-7.80 (m,3H), 6.61 (s, 1H), 4.42-4.30 (m, 1H), 3.90 (quin, J = 8.5 Hz, 1H), 2.64(t, J = 11.6 Hz, 1H), 2.57 (br. s., 1H), 2.45-2.32 (m, 3H), 2.30-2.19(m, 2H), 2.13-2.03 (m, 1H) 347

5-chloro-6-hydroxy-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)nicotinamide 411.1 E: 1.22 F: 1.23 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.43 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.6 Hz,1H), 8.15 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.94-7.88 (m,1H), 7.88-7.79 (m, 2H), 4.37-4.15 (m, 1H), 3.88 (quin, J = 8.5 Hz, 1H),2.64-2.54 (m, 2H), 2.42-2.29 (m, 3H), 2.25- 2.13 (m, 2H), 2.03-1.93 (m,1H) 348

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-4-(1H-1,2,4-triazol-1- yl)benzamide 426.9 E: 1.32 F: 1.34 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 9.37 (s, 1H), 8.71 (d, J = 7.3 Hz, 1H), 8 27(s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.06-7.99 (m, 2H), 7.98-7.94 (m, 2H),7.93-7.81 (m, 3H), 4 42-4.28 (m, 1H), 3.90 (quin, J = 8.5 Hz, 1H),2.67-2.60 (m, 1H), 2.57 (br. s., 1H), 2.44- 2.32 (m, 3H), 2.30-2.20 (m,2H), 2.12-2.03 (m, 1H) 349

3-methoxy-4-(4-methyl- 1H-imidazol-1-yl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)benzamide 470.2 E: 1.20F: 1.48 (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H),8.25 (d, J = 7.6 Hz, 1H), 7.99-7.79 (m, 4H), 7.61 (s, 1H), 7.56-7.50 (m,1H), 7.46 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 4.41-4.28 (m, 1H), 3.95-3.89 (m, 1H), 3.88 (s, 3H), 2.70-2.55 (m, 2H), 2.43-2.32 (m, 3H), 2.24(t, J = 9.6 Hz, 2H), 2.16 (s, 3H), 2.11-2.02 (m, 1H) 350

3-methoxy-4-(2- methylthiazol-5-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)benzamide 487.1 E: 1.40F: 1.68 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.67 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.96-7.88 (m, 1H), 7.88-7.81 (m,2H), 7.79 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H),4.35 (sxt, J = 8.1 Hz, 1H), 3.95 (s, 3H), 3.89 (quin, J = 8.5 Hz, 1H),2.65 (s, 3H), 2.69-2.56 (m, 2H), 2.43-2.29 (m, 3H), 2.28-2.18 (m, 2H),2.08 (t, J = 10.1 Hz, 1H) 351

5-methoxy-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)picolinamide 390.9 E: 1.53 F: 1.56 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 2.7 Hz,1H), 8.24 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.93-7.88 (m,1H), 7.87-7.80 (m, 2H), 7 51 (dd, J = 8.5, 2.7 Hz, 1H), 4.42-4.23 (m,1H), 3.87 (s, 3H), 3.94-3.81 (m, 1H), 2.62- 2.52 (m, 2H), 2.42-2.25 (m,4H), 2.24-2.14 (m, 1H), 2.14-2.06 (m, 1H) 352

3-(1H-imidazol-1-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 426.2 E: 1.13 F: 1.38 (500 MHz,DMSO-d₆) δ 12.48 (s, 1H), 8.72 (d, J = 7.0 Hz, 1H), 8.33 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 8.02 (s, 1H), 7.95-7.89 (m, 1H), 7.88-7.74 (m, 5H),7.64-7.57 (m, 1H), 7.16 (s, 1H), 4.42-4.29 (m, 1H), 3.90 (quin, J = 8.4Hz, 1H), 2.69-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.44-2.30 (m, 3H),2.29-2.19 (m, 2H), 2.11-2.02 (m, 1H) 353

3-cyano-4-isopropoxy-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 443.1 F: 1.60 (500 MHz, DMSO-d₆) δ12.49 (s, 1H), 8.63 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.20(s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.95-7.79 (m, 3H), 7.34 (d, J = 9.0Hz, 1H), 4.94-4.78 (m, 1H), 4.39-4.22 (m, 1H), 3.89 (t, J = 8.3 Hz, 1H),2.61 (br. s., 2H), 2.43-2.28 (m, 3H), 2.22 (d, J = 9.3 Hz, 2H), 2.03 (t,J = 9.9 Hz, 1H), 1.32 (d, J = 5.9 Hz, 6H) 354

3-(difluoromethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 426.0 F: 1.52 (500 MHz, DMSO-d₆) δ12.49 (s, 1H), 8.70 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H),7.98-7.79 (m, 3H), 7.73 (d, J = 7.7 Hz, 1H), 7.63 (br. s., 1H), 7.52 (t,J = 7.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 74.2 Hz, 1H),4.41-4.26 (m, 1H), 3.97-3.81 (m, 1H), 2.67-2.55 (m, 2H), 2.44-2.31 (m,3H), 2.28-2.18 (m, 2H), 2.07 (t, J = 10.0 Hz, 1H) 355

4-ethoxy-5-oxo-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)-1- (2.2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-3- carboxamide 490.8 F: 1.56 (500 MHz, DMSO-d₆) δ12.48 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.97- 7.77 (m, 4H), 4.49 (q, J= 6.9 Hz, 2H), 4.30-4.16 (m, 3H), 4.11 (s, 2H), 3.88 (quin, J = 8.3 Hz,1H), 2.60 (br. s., 1H), 2.42-2.29 (m, 3H), 2.22 (br. s., 1H), 2.15 (t, J= 9.6 Hz, 1H), 1.97 (t, J = 9.8 Hz, 1H), 1.28 (t, J = 6.9 Hz, 3H) 356

6-(dimethylamino)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)nicotinamide 404.1 E: 1.25 (500 MHz, DMSO-d₆)δ 12.48 (s, 1H), 8.56 (br s, 1H), 8.33 (d, J = 7.l Hz, 1H), 8.25 (d, J =7.8 Hz, 1H), 7.99-7.78 (m, 4H), 6.65 (d, J = 9.1 Hz, 1H), 4.40-4.25 (m,1H), 3.89 (t, J = 8.3 Hz, 1H), 3.07 (s, 6H), 2.64-2.54 (m, 2H),2.42-2.29 (m, 3H), 2.25-2.12 (m, 2H), 2.03 (t, J = 9.9 Hz, 1H) 357

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-4-(1H-pyrazol-3- yl)benzamide 426.4 E: 1.31 F: 1.40 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H),8.01-7.68 (m, 8H), 6.80 (s, 1H), 4.44-4.24 (m, 1H), 4.01-3.78 (m, 1H),2.67-2.56 (m, 2H), 2.45-2.32 (m, 3H), 2.29-2.18 (m, 2H), 2.08 (t, J =9.9 Hz, 1H) 358

4-(oxazol-5-yl)-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 427.1 E: 1.40 F: 1.47 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.66 (d, J = 7.5 Hz, 1H), 8.49 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 7.98-7.76 (m, 8H), 4.43-4.29 (m, 1H), 3.99-3.82 (m,1H), 2.67-2.55 (m, 2H), 2.44-2.52 (m, 3H), 2.29 -2.19 (m, 2H), 2.08 (t,J = 10.1 Hz, 1H) 359

4-(1H-imidazol-1-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)benzamide 426.1 E: 1.08 F: 1.35 (500 MHz,DMSO-d₆) δ 12.47 (s, 1H), 8.66 (d, J = 7.3 Hz, 1H), 8.41 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.95-7.81 (m, 4H), 7.77(d, J = 8.5 Hz, 2H), 7.16 (s, 1H), 4.43-4.30 (m, 1H), 3.90 (t, J = 8.4Hz, 1H), 2.69-2.56 (m, 2H), 2.45-2.33 (m, 3H), 2.30- 2.19 (m, 2H), 2.09(t, J = 9.8 Hz, 1H) 360

4-(5-methyl-1,2,4- oxadiazol-3-yl)-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)benzamide 442.2 E: 1.52F: 1.58 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.76 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.9 Hz, 1H), 8.09-8.04 (m, 2H), 8.03-7.97 (m, 2H), 7.95-7.80 (m, 3H), 4.43-4.30 (m, 1H), 3.90 (t, J = 8.4 Hz, 1H), 2.68 (s, 3H),2.65-2.55 (m, 2H), 2.44-2.32 (m, 3H), 2.30-2.19 (m, 2H), 2.13-2.02 (m,1H) 361

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-3-(1H-pyrazol-3- yl)benzamide 426.1 E: 1.34 F: 1.43 (500 MHz, DMSO-d₆) δ12.47 (s, 1H), 8.66 (d, J = 7.0 Hz, 1H), 8.20 (d, J = 7.6 Hz, 2H),8.00-7.69 (m, 6H), 7 48 (br. s., 1H), 6.77 (s, 1H), 4.38 (sxt, J = 8.1Hz, 1H), 3.91 (quin, J = 8.4 Hz, 1H), 2.69-2.56 (m, 2H), 2.45-2.32 (m,3H), 2.30-2.19 (m, 2H), 2.10 (t, J = 9.9 Hz, 1H) 362

8-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a]pyridine- 2-carboxamide 414.2E: 1.11 F: 1.53 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.41 (d, J = 6.7 Hz,1H), 8.32 (s, 1H), 8.31-8.28 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.96-7.79 (m, 3H), 7.13 (d, J = 6.7 Hz, 1H), 6.87 (t, J = 6.9 Hz, 1H),4.46-4.32 (m, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.65-2.56 (m, 2H), 2.53(s, 3H), 2.44-2.30 (m, 4H), 2.26-2.13 (m, 2H) 363

6-bromo-N-((aR)-6-(4-oxo- 3.4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a]pyridine- 2-carboxamide 477.9 E:1.32 F: 1.60 (500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.93 (s, 1H), 8.55 (d,J = 8.2 Hz, 1H), 8.29 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.96-7.79 (m,3H), 7.57 (d, J = 9.8 Hz, 1H), 7.46 (d, J = 9.5 Hz, 1H), 4.36 (sxt, J =8.2 Hz, 1H), 3.88 (quin, J = 8.5 Hz, 1H), 2.61-2.54 (m, 2H), 2.44-2.27(m, 4H), 2.24-2.09 (m, 2H) 364

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-3-carboxamide 413.2 E: 1.62 F:1.63 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.12(d, J = 7.9 Hz, 1H), 8.03-7.95 (m, 2H), 7.94-7.78 (m, 3H), 7.47 (d, J =7.9 Hz, 1H), 7.25-7.16 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 4.44- 4.30 (m,1H), 3.97-3.85 (m, 1H), 3.82 (s, 3H), 2.67-2.54 (m, 2H), 2.45-2.31 (m,3H), 2.28-2.15 (m, 2H), 2.03 (t, J = 10.1 Hz, 1H) 365

5-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 2-(pyridin-4-yl)thiazole-4- carboxamide458.2 E: 1.22 F: 1.69 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.73 (br s,2H), 8.60 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.98 (d, J =4.9 Hz, 2H), 7.94- 7.79 (m, 3H), 4.37 (sxt, J = 8.3 Hz, 1H), 3.91 (quin,J = 8.4 Hz, 1H), 2.80 (s, 3H), 2.66-2.55 (m, 2H), 2.45-2.30 (m, 4H),2.26-2.13 (m, 2H) 366

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indazole-6- carboxamide 414.3 E: 1.40(500 MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.69 (d, J = 7.3 Hz, 1H), 8.25 (d, J= 7.8 Hz, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.97-7.75 (m, 4H), 7.60 (d, J= 8.4 Hz, 1H), 4.40 (sxt, J = 8.1 Hz, 1H), 4.10 (s, 3H), 3.91 (quin, J =8.4 Hz, 1H), 2.65 (t, J = 10.7 Hz, 1H), 2.57 (d, J = 10.9 Hz, 1H),2.46-2.33 (m, 3H), 2.31-2.21 (m, 2H), 2.10 (t, J = 10.0 Hz, 1H) 367

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-6-carboxamide 413.3 E: 1.60 (500MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.25 (d, J =7.7 Hz, 1H), 7.98 (s, 1H), 7.95-7.80 (m, 3H), 7.56 (s, 2H), 7.46 (d, J =2.8 Hz, 1H), 6.46 (br. s., 1H), 4.39 (d, J = 7.9 Hz, 1H), 3.94-3.88 (m,1H), 3.83 (s, 3H), 2.64 (br. s., 1H), 2.60-2.55 (m, 1H), 2.43-2.33 (m,3H), 2.29-2.19 (m, 2H), 2.11-2.05 (m, 1H) 368

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-5-carboxamide 413.3 E: 1.55 (500MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.25 (d, J =7.8 Hz, 1H), 8.13 (s, 1H), 7.97-7.79 (m, 3H), 7.69 (d, J = 8.6 Hz, 1H),7 46 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 2.6 Hz,1H), 4.46-4.32 (m, 1H), 3.90 (quin, J = 8,4 Hz, 1H), 3.81 (s, 3H), 2.60(d, J = 13.0 Hz, 2H), 2.45-2.32 (m, 3H), 2.30-2.17 (m, 2H), 2.13-2.02(m, 1H) 369

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(pyrrolidin-1- yl)picolinamide 430.1 E: 1.44 F: 1.89 (500 MHz, DMSO-d₆)δ 12.46 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.98-7.64 (m, 5H), 6.95 (d, J = 6.4 Hz, 1H), 4.41-4.23 (m, 1H),3.99-3.76 (m, 1H), 3.39-3.26 (m, 4H), 2.57 (br. s., 2H), 2.44-2.31 (m,3H), 2.31-2.24 (m, 1H), 2.19 (br. s., 1H), 2.13- 2.04 (m, 1H), 1.97 (br.s., 4H) 370

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-5-(trifluoromethyl) picolinamide 429.0 E: 1.88 F: 1.89 (500 MHz, DMSO-d₆)δ 12.46 (s, 1H), 9.10 (d, J = 7.9 Hz, 1H), 9.02 (s, 1H), 8.41 (d, J =8.2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H),7.96-7.79 (m, 3H), 4.45-4.32 (m, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.58(d, J = 8.9 Hz, 2H), 2.45-2.29 (m, 4H), 2.26- 2.13 (m, 2H) 371

5-cyano-6-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)picolinaimde 400.3 E: 1.67 F: 1.69 (500 MHz,DMSO-d₆) δ 12.48 (s, 1H), 8.97 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.9 Hz,1H), 8.27 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.93 (d, J =7.3 Hz, 1H), 7.90-7.82 (m, 2H), 4.46-4.31 (m, 1H), 3.91 (quin, J = 8.3Hz, 1H), 2.78 (s, 3H), 2.60 (d, J = 7.9 Hz, 2H), 2.47-2.31 (m, 4H),2.27-2.13 (m, 2H) 372

7-methoxy-3-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indole-2-carboxamide 443.1 E: 1.81 F: 1.84(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 11.02 (s, 1H), 8.31 (d, J = 6.7 Hz,1H), 8.26 (d, J = 7.9 Hz, 1H), 7.97-7.80 (m, 3H), 7.16 (d, J = 7.9 Hz,1H), 6.99-6.92 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.40-4.26 (m, 1H),3.94 (s, 3H), 3.92-3.88 (m, 1H), 2.67 (br. s., 1H), 2.57 (br. s., 1H),2.49 (br. s., 3H), 2.45-2.34 (m, 3H), 2.29 (d, J = 5.8 Hz, 1H), 2.17 (t,J = 9.8 Hz, 1H), 2.00 (t, J = 9.9 Hz, 1H) 373

1-methyl-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)- 1H-indazole-5- carboxamide 414.1 E: 1.46 F:1.42 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.32(s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.98-7.79 (m, 4H), 7.67(d, J = 8.9 Hz, 1H), 4.38 (sxt, J = 7.9 Hz, 1H), 4.06 (s, 3H), 3.90(quin, J = 8.5 Hz, 1H), 2.68-2.54 (m, 2H), 2.46-2.32 (m, 3H), 2.30- 2.18(m, 2H), 2.09 (t, J = 9.8 Hz, 1H) 374

7-bromo-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a]pyridine- 2-carboxamide 478.1 E:1.38 F: 1.59 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.92 (s, 1H), 8.54 (d,J = 8.2 Hz, 1H), 8.29 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.95-7.88 (m,1H), 7.88-7.79 (m, 2H), 7.57 (d, J = 9.5 Hz, 1H), 7.45 (d, J = 9.5 Hz,1H), 4.42-4.28 (m, 1H), 3.88 (quin, J = 8.4 Hz, 1H), 2.57 (br. s., 2H),2.43-2.27 (m, 4H), 2.24-2.10 (m, 2H) 375

5-bromo-N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)picolinaimde 438.9 E: 1.78 F: 1.82 (500 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.76 (s, 1H), 8.24(t, J = 6.9 Hz, 2H), 7.99-7.78 (m, 4H), 4.44-4.29 (m, 1H), 3.92-3.84 (m,1H), 2.62-2.54 (m, 2H), 2.44-2.29 (m, 4H), 2.24-2.11 (m, 2H)

Example 376:7-morpholino-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide,TFA salt

To a solution of Intermediate 2 (21 mg, 0.082 mmol) in toluene (2 mL)was Me₃Al (2 M solution in toluene, 0.12 mL, 0.25 mmol) dropwise at it.After stirring at rt for 5 min, Intermediate 114 (23 mg, 0.082 mmol) wasadded. The reaction was stirred under N₂ at reflux for 1 h. After cooledto rt. TFA and MeOH were carefully added to quench the reaction. Thesolvent was removed. The crude product was purified by reverse phaseHPLC to provide Example 376 (24 mg, 47%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.27 (d, J=7.9 Hz, 1H), 8.85 (d, J=7.3Hz, 1H), 8.43 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.97-7.78 (m, 3H), 7.38(dd, J=8.0, 2.5 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 4.35 (sxt, J=7.9 Hz,1H), 3.91 (quin, J=8.4 Hz, 1H), 3.80-3.66 (m, 4H), 3.55-3.42 (m, 4H),2.72-2.54 (m, 2H), 2.44-2.36 (m, 3H), 2.33-2.18 (m, 2H), 2.11-2.00 (m,1H). LC-MS(ESI) m/z: 485.1 [M+H]⁺. Analytical HPLC RT=4.34 min (MethodA), 6.61 min (Method B).

Examples in Table 22 were prepared by following a similar procedure tothat described in Example 376 by reacting Intermediate 2 with theappropriate esters.

TABLE 22 HPLC Method, LCMS RT Ex. Structure Name [M + H]⁺ (min.) ¹H NMR(δ NMR) 377

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a] pyridine-2- carboxamide 400.1 E: 1.06 F: 1.38 (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.57 (d, J = 7.0 Hz, 1H), 8.48 (d, J =8.2 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.96-7.80 (m, 3H),7.58 (d, J = 9.2 Hz, 1H), 7.39-7.29 (m, 1H), 6.97 (t, J = 6.7 Hz, 1H),4.43-4.28 (m, 1H), 3.89 (quin, J = 8.5 Hz, 1H), 2.56 (d, J = 7.3 Hz,2H), 2.44-2.28 (m, 4H), 2.23-2.08 (m, 2H) 378

7-(4-methylpiperazin- 1-yl)-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide) 498.1E: 1.06 F: 1.34 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.17 (d, J = 7.6 Hz,1H), 8.35 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H),7.96-7.77 (m, 3H), 7.02 (d, J = 8.2 Hz, 1H), 6.81 (br. s., 1H),4.43-4.28 (m, 1H), 3.90 (quin, J = 8.6 Hz, 1H), 3.50-3.00 (m, 4H),2.75-2.55 (m, 6H), 2.45-2.31 (m, 6H), 2.29-2.17 (m, 2H), 2.05 (t, J =9.9 Hz, 1H) 379

7cyano-N-((aR)-6-(4- oxo-3,4- dihydrophathalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 425.1E: 1.41 F: 1.55 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.53 (d, J = 7.0 Hz,1H), 8.82 (d, J = 7.3 Hz, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.25 (d, J =7.9 Hz, 1H), 7.96-7.81 (m, 3H), 7.40 (d, J = 7.0 Hz, 1H), 4.46-4.32 (m,1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.70-2.62 (m, 1H), 2.62- 2.55 (m, 1H),2.45-2.34 (m, 3H), 2.31-2.21 (m, 2H), 2.13-2.03 (m, 1H) 380

8-cyano-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 425.0E: 1.45 F: 1.53 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.68 (d, J = 6.7 Hz,1H), 8.79 (d, J = 7.3 Hz, 1H), 8.48 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),8.15 (d, J = 7.0 Hz, 1H), 7.96-7.80 (m, 3H), 7.26 (t, J = 7.2 Hz, 1H),4.47-4.32 (m, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.71-2.62 (m, 1H), 2.58(t, J = 7.8 Hz, 1H), 2.46-2.34 (m, 3H), 2.31-2.21 (m, 2H), 2.14-2.05 (m,1H) 381

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-8-(trifluoromethyl) imidazo[1,2-a] pyridine-3- carboxamide 468.0 E:1.58 F: 1.73 (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.67 (d, J = 6.7 Hz,1H), 8.77 (d, J = 7.3 Hz, 1H), 8.45 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),7.96- 7.80 (m, 4H), 7.25 (t, J = 7.0 Hz, 1H), 4.40 (sxt, J = 7.9 Hz,1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.70- 2.62 (m, 1H), 2.62-2.54 (m, 1H),2.45-2.33 (m, 3H), 2.31-2.22 (m, 2H), 2.14-2.05 (m, 1H) 382

8-chloro-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 434.0E: 1.36 F: 1.61 (500 MHz, DMSO-d₆) δ (2.47 (s, 1H), 9.43 (d, J = 7.0 Hz,1H), 8.71 (d, J = 7.3 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),7.98- 7.77 (m, 3H), 7.65 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H),4.48-4.27 (m, 1H), 3.91 (quin, J = 8.4 Hz, 1H), 2.66 (t, J = 11.4 Hz,1H), 2.58 (t, J = 8.1 Hz, 1H), 2.46-2.33 (m, 3H), 2.31-2.21 (m, 2H),2.08 (t, J = 9.9 Hz, 1H) 383

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-7-phenylimidazo [1,2-a]pyridine-3- carboxamide 476.0 E: 1.54 F: 1.91(500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.52 (d, J = 7.3 Hz, 1H), 8.71 (d, J= 7.3 Hz, 1H), 846 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.06 (s, 1H),7.97-7.79 (m, 5H), 7.61 (d, J = 7.0 Hz, 1H), 7.57-7.50 (m, 2H),7.50-7.44 (m, 1H), 4.41 (sxt, J = 8.0 Hz, 1H), 3.91 (quin, J = 8.4 Hz,1H), 2.71-2.63 (m, 1H), 2.59 (t, J = 7.9 Hz, 1H), 2.46- 2.34 (m, 3H),2.33-2.21 (m, 2H), 2.09 (t, J = 9.9 Hz, 1H) 384

7-(benzyloxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide 506.1E: 1.62 F: 1.94 (500 MHz, DMSO-d₆) δ (2.48 (s, 1H), 9.26 (d, J = 7.6 Hz,1H), 8.48 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H),7.95-7.80 (m, 3H), 7.52-7.45 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.37-7.32 (m, 1H), 7.14 (d, J = 1.8 Hz, 1H), 6.87 (dd, J = 7.6, 2.1 Hz, 1H),5.20 (s, 2H), 4.35 (sxt, J = 7.9 Hz, 1H), 3.89 (quin, J = 8.5 Hz, 1H),2.63 (t, J = 11.4 Hz, 1H), 2.57 (br. s., 1H), 2.43-2.32 (m, 3H),2.28-2.18 (m, 2H), 2.09-2.01 (m, 1H) 385

7-methoxy-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide 430.0E: 1.32 F: 1.58 (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.39 (d, J = 7.9 Hz,1H), 8.80 (d, J = 7.3 Hz, 1H), 8.44 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.97- 7.79 (m, 3H), 7.25 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 7.8, 2.3 Hz,1H), 4.44-4.30 (m, 1H), 3.95 (s, 3H), 3.93-3.85 (m, 1H), 2.65 (d, J =11.6 Hz, 1H), 2.61-2.55 (m, 1H), 2.45-2.34 (m, 3H), 2.31-2.19 (m, 2H),2.06 (t, J = 9.9 Hz, 1H) 386

8-chloro-7-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 448.2E: 1.44 F: 1.77 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.56 (s, 1H), 8.71(d, J = 7.3 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.96-7.89(m, 1H), 7.89-7.80 (m, 2H), 7.77 (s, 1H), 4.37 (sxt, J = 8.0 Hz, 1H),3.90 (quin, J = 8.4 Hz, 1H), 2.70-2.62 (m, 1H), 2.57 (d, J = 11.0 Hz,1H), 2.44 (s, 3H), 2.42-2.34 (m, 3H), 2.30-2.21 (m, 2H), 2.07 (t, J =10.1 Hz, 1H) 387

7-fluoro-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 418.0E: 1.20 F: 1.83 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.47 (t, J = 6.9 Hz,1H), 8.61 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.96- 7.80 (m, 3H), 7.56 (dd, J = 9.6, 2.3 Hz, 1H), 7.20-7.10 (m, 1H),4.37 (sxt, J = 8.0 Hz, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.68-2.61 (m,1H), 2.57 (d, J = 10.7 Hz, 1H), 2.44-2.33 (m, 3H), 2.29-2.20 (m, 2H),2.11-2.02 (m, 1H) 388

3-isopropyl-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-5,6,7,8- tetrahydroimidazo [1,5-a]pyridine-1-carboxamide 446.0 E: 1.27 F: 1.71 (500 MHz, DMSO-d₆) δ 12.46 (s, 1H),8.25 (d, J = 7.6 Hz, 1H), 7.94-7.88 (m, 1H), 7.88-7.79 (m, 2H), 7.54(br. s., 1H), 4.36-4.20 (m, 1H), 3.94-3.81 (m, 3H), 3.07-2.96 (m, 1H),2.92 (t, J = 6.3 Hz, 2H), 2.60-2.54 (m, 2H), 2.43-2.29 (m, 3H), 2.26-2.12 (m, 2H), 2.08-1.99 (m, 1H), 1.85 (d, J = 4.3 Hz, 2H), 1.70 (br. s.,2H), 1.22 (d, J = 6.7 Hz, 6H) 389

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-[1,2,4]triazolo [4,3-a]pyridine-3- carboxamide 401.2 E: 1.33 F: 1.37(500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.37 (d, J = 7.6 Hz, 1H), 9.19 (d, J= 6.7 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.97-7.80 (m, 4H), 7.59-7.52(m, 1H), 7.19 (t, J = 6.9 Hz, 1H), 4.49-4.35 (m, 1H), 3.90 (quin, J =8.4 Hz, 1H), 2.66-2.56 (m, 2H), 2.45-2.32 (m, 4H), 2.22 (d, J = 8.2 Hz,2H) 390

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6-(trifluoromethyl) imidazol[1,2-a] pyridine-3- carboxamide 468.0 E:1.54 F: 1.78 (500 MHz, DMSO-d₆) δ (2.47 (s, 1H), 9.92 (br s, 1H), 8.81(d, J = 7.3 Hz, 1H), 8.50 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.97-7.79(m, 4H), 7.71 (d, J = 9.5 Hz, 1H), 4.39 (sxt, J = 7.8 Hz, 1H), 3.91(quin, J = 8.3 Hz, 1H), 2.66 (br. s., 1H), 2.58 (br. s., 1H), 2.45- 2.33(m, 3H), 2.32-2.21 (m, 2H), 2.09 (t, J = 10.1 Hz, 1H)

The Examples in Table 23 were prepared by using the similar procedure tothat described in Example 1. Intermediate 2 was coupled with theappropriate acid intermediates. Various coupling reagents could be usedother than the one described in Example 1 such as BOP, PyBop, EDC/HOBtor HATU.

TABLE 23 HPLC Method, LCMS RT Ex. Structure Name [M + H]⁺ (min.) ¹H NMR(δ NMR) 391

7-(4,4- difluoropiperidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 519.2 A: 5.23 B: 7.75 (400 MHz, CD₃OD) δ 9.33(d, J = 8.1 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.26 (s, 1H), 7.99-7.80(m, 3H), 7.34 (dd, J = 8.0, 2.5 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 4.45(quin, J = 8.2 Hz, 1H), 3.96 (quin, J = 8.4 Hz, 1H), 3.83-3.71 (m, 4H),2.81-2.71 (m, 1H), 2.70- 2.61 (m, 1H), 2.61-2.52 (m, 1H), 2.52-2.35 (m,3H), 2.32-2.23 (m, 1H), 2.21-2.06 (m, 5H) 392

7-(3,3- difluoropyrrolidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 505.1 E: 1.38 F: 1.62 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.29 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 7.4 Hz, 1H), 8.44 (s,1H), 8.25 (d, J = 8.0 Hz, 1H), 7.95-7.89 (m, 1H), 7.88-7.80 (m, 2H),7.08-7.03 (m, 1H), 6.66 (s, 1H), 4.43-4.27 (m, 1H), 3.97 (t, J = 12.9Hz, 2H), 3.90 (t, J = 8.3 Hz, 1H), 3.71 (t, J = 7.2 Hz, 2H), 2.71-2.57(m, 4H), 2.45-2.35 (m, 3H), 2.31- 2.18 (m, 2H), 2.06 (t, J = 10.2 Hz,1H) 393

7-((R)-3- fluoropyrrolidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 487.1 E: 1.33 F: 1.50 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.19 (d, J = 7.4 Hz, 1H), 8.34 (d, J = 7.4 Hz, 1H), 8.25 (d, J= 7.7 Hz, 1H), 8.13 (s, 1H), 7.95-7.90 (m, 1H), 7.89-7.81 (m, 2H), 6.75(d, J = 8.3 Hz, 1H), 6.44 (s, 1H), 5.58-5.38 (m, 1H), 4.41-4.28 (m, 1H),3.93-3.86 (m, 1H), 3.65 (br. s., 1H), 3.61-3.51 (m, 2H), 3.44 (d, J =8.5 Hz, 1H), 2.69- 2.56 (m, 2H), 2.44-2.35 (m, 3H), 2.31-2.17 (m, 4H),2.08-1.98 (m, 1H) 394

7-((S)-3- fluoropyrrolidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 487.1 E: 1.33 F: 1.51 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.18 (d, J = 7.4 Hz, 1H), 8.26 (t, J = 8.9 Hz, 2H), 8.10 (s,1H), 7.96-7.89 (m, 1H), 7.89- 7.81 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H),6.42 (s, 1H), 5.60-5.37 (m, 1H), 4.36 (q, J = 8.0 Hz, 1H), 3.90 (t, J =7.7 Hz, 1H), 3.69-3.60 (m, 1H), 3.58-3.50 (m, 2H), 3.48- 3.40 (m, 1H),2.68-2.56 (m, 2H), 2.46-2.34 (m, 3H), 2.31-2.14 (m, 4H), 2.08-1.99 (m,1H) 395

7-((R)-3- hydroxypyrrolidin-1- yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 485.1 E: 1.20 F: 1.34 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.15 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 7.3 Hz, 1H), 8.25 (d, J= 7.9 Hz, 1H), 8.10 (s, 1H), 7.96-7.89 (m, 1H), 7.89-7.80 (m, 2H), 6.69(d, J = 7.3 Hz, 1H), 6.34 (s, 1H), 4.42 (br. s., 1H), 4.39-4.28 (m, 1H),3.90 (quin, J = 8.4 Hz, 1H), 3.55-3.32 (m, 3H), 3.20 (d, J = 10.4 Hz,1H), 2.69-2.56 (m, 2H), 2.44-2.30 (m, 3H), 2.28-2.15 (m, 2H), 2.11-1.98(m, 2H), 1.92 (d, J = 11.6 Hz, 1H) 396

7-((2-hydroxyethyl) (methyl)amino)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 473.1 E: 1.19 F: 1.32 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.15 (d, J = 7.9 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.33- 8.19(m, 2H), 7.99-7.73 (m, 3H), 7.05 (d, J = 7.6 Hz, 1H), 6.60 (br. s., 1H),4.45-4.24 (m, 1H), 3.99-3.82 (m, 1H), 3.60 (br. s., 2H), 3.56 (d, J =4.9 Hz, 2H), 3.07 (s, 3H), 2.64 (br. s., 1H), 2.57 (br. s., 1H),2.45-2.32 (m, 3H), 2.30-2.18 (m, 2H), 2.09-1.99 (m, 1H) 397

7-((2-methoxyethyl) (methyl)amino)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 487.1 E: 1.32 F: 1.47 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.20 (d, J = 8.2 Hz, 1H), 8.86 (d, J = 7.0 Hz, 1H), 8.40 (s,1H), 8.26 (d, J = 7.9 Hz, 1H), 7.97-7.77 (m, 3H), 7.21 (d, J = 7.6 Hz,1H), 6.71 (br. s., 1H), 4.43-4.26 (m, 1H), 3.91 (t, J = 8.2 Hz, 1H),3.72 (br. s., 2H), 3.55 (br. s., 2H), 3.25 (s, 3H), 3.11 (s, 3H), 2.66(br. s., 1H), 2.58 (br. s., 1H), 2.45-2.33 (m, 3H), 2.31-2.18 (m, 2H),2.05 (t, J = 9.9 Hz, 1H) 398

7-(2- morpholinoethoxy)-N- ((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide529.0 E: 1.09 F: 1.42 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.27 (d, J =7.7 Hz, 1H), 8.45 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.21(s, 1H), 7.95-7.79 (m, 3H), 7.10 (br. s., 1H), 6.81 (d, J = 8.3 Hz, 1H),4.41-4.32 (m, 1H), 4.24 (br. s., 2H), 3.90 (t, J = 8.4 Hz, 1H), 3.62(br. s., 4H), 3.01-2.54 (m, 8H), 2.43-2.35 (m, 3H), 2.29-2.18 (m, 2H),2.06 (t, 10.0 Hz, 1H) 399

7-((2-hydroxy-2- methylpropyl) (methyl)amino)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 501.1 A: 4.44 B: 6.46 (400 MHz, CD₃OD) δ 9.22(d, J = 7.9 Hz, 1H), 8.44-8.31 (m, 1H), 8.20 (s, 1H), 7.97-7.76 (m, 3H),7.26 (dd, J = 7.8, 2.3 Hz, 1H), 6.75 (br. s., 1H), 4.44 (quin, J = 8.2Hz, 1H), 3.95 (quin, J = 8.4 Hz, 1H), 3.60 (s, 2H), 3.25 (s, 3H),2.80-2.69 (m, 1H), 2.69-2.61 (m, 1H), 2.60-2.51 (m, 1H), 2.51-2.34 (m,3H), 2.27 (dd, J = 10.8, 9.0 Hz, 1H), 2.10 (dd, J = 11.2, 9.0 Hz, 1H),1.27 (s, 6H) 400

7-(2-hydroxy-2- methylpropoxy)-N- ((aR)-6-(4-oxo- 3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide488.1 A: 4.29 B: 6.22 (400 MHz, CD₃OD) δ 9.54 (d, J = 7.7 Hz, 1H), 8.41(s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.97- 7.80 (m, 3H), 7.30 (d, J = 2.2Hz, 1H), 7.27 (dd, J = 7.7, 2.6 Hz, 1H), 4.47 (quin, J = 8.2 Hz, 1H),4.05 (s, 2H), 3.96 (quin, J = 8.4 Hz, 1H), 2.82-2.71 (m, 1H), 2.70-2.61(m, 1H), 2.61-2.52 (m, 1H), 2.52-2.37 (m, 3H), 2.29 (dd, J = 10.8, 9.0Hz, 1H), 2.12 (dd, J = 11.2, 9.0 Hz, 1H), 1.36 (s, 6H) 401

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-7-(2-(pyrrolidin- 1-yl)ethoxy)imidazol [1,2-a]pyridine-3-carboxamide 513.1 E: 1.11 F: 1.26 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H),9.26 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.9 Hz,1H), 8.21 (s, 1H), 7.96-7.79 (m, 3H), 7.08 (br. s., 1H), 6.81 (d, J =7.6 Hz, 1H), 4.43-4.31 (m, 1H), 4.20 (br. s., 2H), 3.91 (t, J = 8.2 Hz,1H), 3.34 (br. s., 4H), 2.91 (br. s., 2H), 2.70-2.54 (m, 2H), 2.45- 2.32(m, 3H), 2.29-2.18 (m, 2H), 2.06 (t, J = 9.8 Hz, 1H), 1.71 (br. s., 4H)402

1-(2-hydroxy-2- methylpropyl)-7-oxo- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)-1,7- dihydroimidazol[1,2-a]pyridine-3- carboxamide 488.1 A: 4.39 B: 6.30 (400 MHz, DMSO-d₆)δ 12.47 (s, 1H), 9.51 (d, J = 7.1 Hz, 1H), 9.06 (d, J = 7.3 Hz, 1H),8.58 (s, 1H), 8.26 (dd, J = 7.8, 0.8 Hz, 1H), 7.97-7.79 (m, 3H), 7.43(d, J = 2.2 Hz, 1H), 7.18 (dd, J = 7.6. 2.3 Hz, 1H), 4.44- 4.31 (m, 1H),4.22 (s, 2H), 3.91 (quin, J = 8.5 Hz, 1H), 2.72- 2.63 (m, 1H), 2.59(ddd, J = 10.9, 8.1, 2.8 Hz, 1H), 2.45-2.37 (m, 3H), 2.33-2.20 (m, 2H),2.11-2.03 (m, 1H), 1.21-1.14 (m, 6H) 403

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-7-(trifluoromethyl) imidazo[1,2-a] pyridine-3- carboxamide 468.0 E:1.53 F: 1.77 (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.61 (d, J = 7.3 Hz,1H), 8.78 (d, J = 7.3 Hz, 1H), 8.51 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),8.19 (s, 1H), 7.95-7.79 (m, 3H), 7.38 (d, J = 5.8 Hz, 1H), 4.46- 4.34(m, 1H), 3.91 (quin, J = 8.4 Hz, 1H), 2.71-2.62 (m, 1H), 2.62-2.55 (m,1H), 2.45-2.33 (m, 3H), 2.31-2.21 (m, 2H), 2.13-2.04 (m, 1H) 404

8-fluoro-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine-3- carboxamide 486.0 E: 1.80 F: 1.87 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.75 (s, 1H), 8.90 (d, J = 7.0 Hz, 1H), 8.50 (s, 1H), 8.25 (d,J = 7.6 Hz, 1H), 7.95- 7.79 (m, 4H), 4.39 (sxt, J = 8.0 Hz, 1H), 3.91(quin, J = 8.5 Hz, 1H), 2.71-2.62 (m, 1H), 2.62- 2.56 (m, 1H), 2.46-2.34(m, 3H), 2.32-2.21 (m, 2H), 2.13-2.06 (m, 1H) 405

6-fluoro-8-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 432.0E: 1.32 F: 1.67 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.33 (br s, 1H),8.65 (d, J = 7.3 Hz, 2H), 8.38 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.97-7.77 (m, 3H), 7.42 (d, J = 8.5 Hz, 1H), 4.46-4.30 (m, 1H), 3.98-3.83 (m,1H), 2.65 (br. s., 1H), 2.61-2.57 (m, 1H), 2.55 (s, 3H), 2.45-2.34 (m,3H), 2.30-2.20 (m, 2H), 2.12-2.04 (m, 1H) 406

7-(difluoromethoxy)- N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 466.0E: 1.33 F: 1.63 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.44 (d, J = 7.6 Hz,1H), 8.59 (d, J = 7.3 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.96-7.79 (m, 3H), 7.43 (s, 1H), 7.47 (t, J = 73.5 Hz, 1H), 7.03 (dd, J= 7.6, 2.4 Hz, 1H), 4.38 (sxt, J = 8.1 Hz, 1H), 3.91 (quin, J = 8.4 Hz,1H), 2.69- 2.61 (m, 1H), 2.61-2.55 (m, 1H), 2.45-2.33 (m, 3H), 2.30-2.19(m, 2H), 2.12-2.02 (m, 1H) 407

6-fluoro-5-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 432.0E: 1.23 F: 1.50 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.93 (d, J = 7.3 Hz,1H), 8.25 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H),7.89-7.79 (m, 2H), 7.63 (dd, J = 9.6, 5.0 Hz, 1H), 7.51 (t, J = 9.2 Hz,1H), 4.38-4.22 (m, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.70-2.61 (m, 1H),2.60-2.55 (m, 1H), 2.54 (s, 3H), 2.44-2.33 (m, 3H), 2.31- 2.20 (m, 2H),2.09-2.01 (m, 1H) 408

6-fluoro-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazo[1,2-a] pyridine-3- carboxamide 418.0E: 1.27 F: 1.54 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.47 (dd, J = 4.9,2.4 Hz, 1H), 8.66 (d, J = 7.3 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.96-7.81 (m, 3H), 7.78 (dd, J = 9.9, 5.3 Hz, 1H), 7.60- 7.51(m, 1H), 4.39 (sxt, J = 8.1 Hz, 1H), 3.91 (quin, J = 8.5 Hz, 1H),2.69-2.62 (m, 1H), 2.61- 2.55 (m, 1H), 2.46-2.33 (m, 3H), 2.31-2.20 (m,2H), 2.13- 2.03 (m, 1H) 409

7-((2-hydroxy-2- methylpropyl)amino)- N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a]pyridine-3- carboxamide 487.1 E: 1.26 F: 1.37 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.10 (d, J = 7.9 Hz, 1H), 8.83 (J = 7.3 Hz, 1H), 8.34 (s, 1H),8.25 (d, J = 7.6 Hz, 1H), 7.97-7.89 (m, 1H), 7.88- 7.79 (m, 2H), 7.65(t, J = 5.5 Hz, 1H), 7.10-7.03 (m, 1H), 6.66 (br. s., 1H), 4.33 (sxt, J= 8.0 Hz, 1H), 3.97-3.82 (m, 1H), 3.11 (d, J = 5.2 Hz, 2H), 2.69- 2.62(m, 1H), 2.60-2.55 (m, 1H), 2.44-2.33 (m, 3H), 2.30-2.18 (m, 2H),2.08-2.00 (m, 1H), 1.18 (s, 6H) 410

6-fluoro-7-methyl-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 432.0E: 1.38 F: 1.67 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.40 (d, J = 5.8 Hz,1H), 8.59 (d, J = 7.3 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),7.95-7.89 (m, 1H), 7.89-7.79 (m, 2H), 7.65 (d, J = 7.0 Hz, 1H), 4.38(sxt, J = 8.1 Hz, 1H), 3.90 (quin, J = 8.5 Hz, 1H), 2.68-2.61 (m, 1H),2.61-2.54 (m, 1H), 2.36 (s, 3H), 2.45-2.32 (m, 3H), 2.30-2.20 (m, 2H),2.07 (t, J = 10.1 Hz, 1H) 411

6,8-difluoro-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 436.0E: 1.58 F: 1.64 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.36 (d, J = 3.1 Hz,1H), 8.77 (d, J = 7.3 Hz, 1H), 8.42 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H),7.96-7.89 (m, 1H), 7.89-7.80 (m, 2H), 7.79-7.71 (m, J = 9.0, 9.0 Hz,1H), 4.38 (sxt, J = 7.9 Hz, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.70-2.62(m, 1H), 2.62- 2.56 (m, 1H), 2.45-2.33 (m, 3H), 2.31-2.21 (m, 2H),2.12-2.03 (m, 1H) 412

7-methyl-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 414.0E: 1.32 F: 1.58 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.31 (d, J = 7.0 Hz,1H), 8.50 (d, J = 7.3 Hz, 1H), 8.27 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),7.96-7.80 (m, 3H), 7.47 (s, 1H), 6.95 (d, J = 6.4 Hz, 1H), 4.38 (sxt, J= 8.1 Hz, 1H), 3.96-3.84 (m, 1H), 2.69-2.61 (m, 1H), 2.61-2.55 (m, 1H),2.39 (s, 3H), 2.45-2.33 (m, 3H), 2.29-2.20 (m, 2H), 2.07 (t, J = 10.1Hz, 1H) 413

8-(benzyloxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 506.3E: 1.40 F: 1.78 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.06 (d, J = 5.2 Hz,1H), 8.60 (d, J = 7.5 Hz, 1H), 8.32- 8.20 (m, 2H), 7.97-7.79 (m, 3H),7.51 (d, J = 7.3 Hz, 2H), 7.46- 7.39 (m, 2H), 7.39-7.32 (m, 1H),7.06-6.92 (m, 2H), 5.30 (s, 2H), 4.45-4.30 (m, 1H), 3.97-3.84 (m, 1H),2.64 (t, J = 11.4 Hz, 1H), 2.60-2.54 (m, 1H), 2.44-2.33 (m, 3H),2.29-2.20 (m, 2H), 2.07 (t, J = 10.0 Hz, 1H) 414

7-(methylthio)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)imidazol[1,2-a] pyridine-3- carboxamide 446.3E: 1.23 F: 1.49 (500 MHz, DMSO-d₆) δ 12.50 (s, 1H), 9.25 (d, J = 7.3 Hz,1H), 8.57 (d, J = 7.1 Hz, 1H), 8.25 (br. s., 2H), 7.96-7.89 (m, 1H),7.88-7.80 (m, 2H), 7.36 (s, 1H), 6.99 (d, J = 6.9 Hz, 1H), 4.42- 4.31(m, 1H), 3.96-3.81 (m, 1H), 2.63 (br. s., 1H), 2.60-2.57 (m, 1H), 2.56(br. s., 3H), 2.43-2.34 (m, 3H), 2.24 (d, J = 7.9 Hz, 2H), 2.05 (t, J =10.0 Hz, 1H) 415

4-oxo-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-4,5,6,7- tetrahydropyrazolo [1,5-a]pyrazine-2- carboxamide 419.4 E:1.10 F: 1.11 (500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.46 (d, J = 7.9 Hz,1H), 8.33 (br. s., 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.96-7.79 (m, 3H),7.02 (s, 1H), 4.42-4.23 (m, 3H), 3.88 (quin, J = 8.5 Hz, 1H), 3.63 (br.s., 2H), 2.58-2.54 (m, 2H), 2.42-2.22 (m, 4H), 2.21-2.13 (m, 1H),2.11-2.03 (m, 1H) 416

3-methoxy-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-4-(1H-pyrazol-4- yl)benzamide 455.9 E: 1.37F: 1.40 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.9 Hz, 1H), 8.12 (s, 2H), 7.96-7.80 (m, 3H), 7.70 (d, J =7.6 Hz, 1H), 7.54-7.43 (m, 2H), 4.43-4.31 (m, 1H), 3.93 (s, 3H),3.92-3.86 (m, 1H), 2.67-2.55 (m, 2H), 2.45-2.35 (m, 3H), 2.30-2.20 (m,2H), 2.09 (t, J = 10.1 Hz, 1H) 417

3-cyano-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-4-(1H-pyrazol-4- yl)benzamide 451.1 E: 1.28F: 1.31 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.79 (d, J = 7.2 Hz, 1H),8.31 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.7 Hz, 1H),8.44-8.04 (br. s, 2H), 7.97-7.78 (m, 4H), 4.43-4.26 (m, 1H), 3.98-3.81(m, 1H), 2.68-2.55 (m, 2H), 2.44-2.31 (m, 3H), 2.25 (t, J = 9.6 Hz, 2H),2.07 (t, J = 10.0 Hz, 1H) 418

3-methyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-4-(1H-pyrazol-4- yl)benzamide 440.1 E: 1.27F: 1.31 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H),8.25 (d, J = 7.8 Hz, 1H), 8.05 (br. s., 1H), 7.94-7.76 (m, 4H), 7.74 (s,1H), 7.66 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 4.45-4.24 (m,1H), 3.90 (t, J = 8.3 Hz, 1H), 2.66-2.55 (m, 2H), 2.42 (s, 3H),2.40-2.31 (m, 3H), 2.28-2.17 (m, 2H), 2.07 (t, J = 9.9 Hz, 1H) 419

2-methoxy-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan-2- yl)-4-(1H-pyrazol-4- yl)benzamide 456.0 F: 1.25(500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.20 (d, J= 7.3 Hz, 1H), 8.08 (br. s., 2H), 7.96-7.81 (m, 3H), 7.70 (d, J = 7.9Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 7.9 Hz, 1H), 4.40-4.25 (m, 1H), 3.96(s, 3H), 3.90 (t, J = 8.5 Hz, 1H), 2.67- 2.54 (m, 2H), 2.43-2.31 (m,3H), 2.25 (br. s., 1H), 2.18 (t, J = 9.6 Hz, 1H), 2.01 (t, J = 9.7 Hz,1H) 420

7-(1-methyl-1H- pyrazol-4-yl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)-1H-indole-2- carboxamide479.2 E: 1.52 F: 1.51 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 10.52 br s,1H), 8.71 (d, J = 6.9 Hz, 1H), 8.35-8.16 (m, 2H), 7.98-7.79 (m, 4H),7.53 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.17 (s, 1H), 7.09(t, J = 7.4 Hz, 1H), 4.45-4.29 (m, 1H), 3.94 (s, 3H), 3.92-3.85 (m, 1H),2.72-2.62 (m, 1H), 2.58 (br. s., 1H), 2.45-2.33 (m, 3H), 2.31-2.19 (m,2H), 2.07 (t, J = 9.9 Hz, 1H) 421

N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-6H-isochromeno [4,3-d]pyrimidine-8- carboxamide 466.2 E: 1.41 F:1.50 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.88 (s, 1H), 8.76 (d, J = 7.3Hz, 1H), 8.53 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.2 Hz,1H), 7.96 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.89-7.81 (m,2H), 7.80 (s, 1H), 5.45 (s, 2H), 4.48-4.25 (m, 1H), 3.90 (t, J = 8.4 Hz,1H), 2.69-2.56 (m, 2H), 2.45-2.32 (m, 3H), 2.30-2.20 (m, 2H), 2.08 (t, J= 9.9 Hz, 1H) 422

3-methoxy-4-(1- methyl-1H-pyrazol- 4-yl)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan-2- yl)benzamide 470.2 E: 1.44F: 1.52 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.53 (d, J = 7.3 Hz, 1H),8.26 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.94-7.79 (m, 3H),7.67 (d, J = 7.9 Hz, 1H), 7.53-7.42 (m, 2H), 4.43-4.29 (m, 1H), 3.93 (s,3H), 3.87 (s, 3H), 4.01-3.81 (m, 1H), 2.68- 2.55 (m, 2H), 2.45-2.33 (m,3H), 2.30-2.19 (m, 2H), 2.09 (t, J = 9.9 Hz, 1H) 423

3-fluoro-4-(1-methyl- 1H-pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)benzamide 458.0 E: 1.55F: 1.55 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.63 (d, J = 7.0 Hz, 1H),8.25 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 8.00-7.94 (m, 1H), 7.94-7.89 (m,1H), 7.88-7.77 (m, 3H), 7.75- 7.67 (m, 2H), 4.34 (sxt, J = 7.8 Hz, 1H),3.90 (s, 3H), 4.01-3.79 (m, 1H), 2.66-2.54 (m, 2H), 2.44- 2.31 (m, 3H),2.28-2.18 (m, 2H), 2.07 (t, J = 10.1 Hz, 1H) 425

6-(1-methyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)nicotinamide 441.0 E:1.20 F: 1.37 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.92 (s, 1H), 8.68 (d,J = 7.3 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.15 (d, J =7.9 Hz, 1H), 8.05 (s, 1H), 7.96-7.80 (m, 3H), 7.72 (d, J = 8.2 Hz, 1H),4.41-4.30 (m, 1H), 3.89 (s, 3H), 3.92 (br. s., 1H), 2.68-2.55 (m, 2H),2.45-2.33 (m, 3H), 2.25 (t, J = 9.3 Hz, 2H), 2.08 (t, J = 9.9 Hz, 1H)426

7-acetyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazo[1,2-a] pyridine-3- carboxamide 442.0E: 1.27 F: 1.48 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.48 (d, J = 7.0 Hz,1H), 8.75 (d, J = 7.3 Hz, 1H), 8.52 (s, 1H), 8.40 (br. s., 1H), 8.26 (d,J = 7.6 Hz, 1H), 7.96-7.78 (m, 3H), 7.50 (d, J = 7.0 Hz, 1H), 4.40 (d, J= 8.2 Hz, 1H), 3.98-3.85 (m, 1H), 2.67 (s, 3H), 2.73-2.63 (m, 1H), 2.59(br. s., 1H), 2.45-2.33 (m, 3H), 2.27 (t, J = 9.0 Hz, 2H), 2.10 (t, J =9.8 Hz, 1H) 427

3-fluoro-4-(1-d3- methyl-1H-pyrazol- 4-yl)-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)benzamide 461.1 E: 1.55F: 1.53 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.62 (d, J = 7.3 Hz, 1H),8.25 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.97 (s, 1H),7.94-7.89 (m, 1H), 7.89-7.78 (m, 3H), 7.75-7.68 (m, 2H), 4.34 (sxt, J =8.1 Hz, 1H), 3.90 (quin, J = 8.5 Hz, 1H), 2.67-2.53 (m, 2H), 2.45-2.32(m, 3H), 2.29-2.19 (m, 2H), 2.12-2.03 (m, 1H) 428

4-(1-(difluoromethyl)- 1H-pyrazol-4-yl)-3- fluoro-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)benzamide 494.3 E: 1.79F: 1.79 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.74 (s, 1H), 8.69 (d, J =7.0 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.04- 7.72 (m, 7H),4.42-4.27 (m, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.68- 2.53 (m, 2H),2.44-2.32 (m, 3H), 2.29-2.19 (m, 2H), 2.12-2.03 (m, 1H) 429

7-(2-hydroxypropan- 2-yl)-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide 458.1E: 1.27 F: 1.45 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.38 (d, J = 7.3 Hz,1H), 8.61 (d, J = 7.6 Hz, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H),7.97-7.80 (m, 3H), 7.70 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 4.47- 4.31(m, 1H), 3.97-3.86 (m, 1H), 2.64 (br. s., 1H), 2.57 (d, J = 11.0 Hz,1H), 2.45-2.34 (m, 3H), 2.30- 2.21 (m, 2H), 2.08 (t, J = 9.9 Hz, 1H),1.47 (s, 6H) 430

7-(1-hydroxyethyl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a] pyridine-3- carboxamide 444.0E: 1.18 F: 1.70 (500 MHz, DMSO-d₆) δ 9.36 (d, J = 7.3 Hz, 1H), 8.53 (d,J = 7.3 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.97-7.80 (m,3H), 7.56 (s, 1H), 7.10 (d, J = 7.0 Hz, 1H), 4.80 (d, J = 6.4 Hz, 1H),4.45-4.32 (m, 1H), 3.97-3.85 (m, 1H), 2.68-2.61 (m, 1H), 2.61-2.55 (m,1H), 2.45-2.35 (m, 3H), 2.29-2.21 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) 431

7-((1,1- dioxidotetrahydro- 2H-thiopyran-4-yl) oxy)-N-((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)imidazo[1,2-a]pyridine-3- carboxamide 548.1 E: 1.43 F: 1.60 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.29 (d, J = 7.3 Hz, 1H), 8.46 (J = 7.3 Hz, 1H), 8.25 (d, J =7.6 Hz, 1H), 8.21 (s, 1H), 7.96-7.79 (m, 3H), 7.24 (br. s., 1H), 6.88(d, J = 7.6 Hz, 1H), 4.89 (br. s., 1H), 4.43-4.31 (m, 1H), 3.90 (quin, J= 8.4 Hz, 1H), 3.22 (br. s., 4H), 2.67-2.56 (m, 2H), 2.45-2.33 (m, 3H),2.24 (d, J = 8.2 Hz, 6H), 2.06 (t, J = 10.1 Hz, 1H) 432

N-((aR)-6-(4- oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan-2-yl)-7-(3,3,3- trifluoropropoxy) imidazo[1,2-a] pyridine-3- carboxamide512.4 A: 5.53 B: 8.11 (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.43 (d, J =7.7 Hz, 1H), 8.82 (d, J = 7.3 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J = 7.9Hz, 1H), 7.96-7.81 (m, 3H), 7.38 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 7.7,2.4 Hz, 1H), 4.44 (t, J = 5.7 Hz, 2H), 4.41-4.31 (m, 1H), 3.91 (quin, J= 8.5 Hz, 1H), 2.90 (qt, J = 11.3, 5.7 Hz, 2H), 2.72-2.63 (m, 1H),2.62-2.54 (m, 1H), 2.44-2.36 (m, 3H), 2.32-2.21 (m, 2H), 2.11-2.03 (m,1H) 433

7-((1,3- difluoropropan-2- yl)oxy)-N-((aR)- 6-(4-oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazol[1,2-a]pyridine-3- carboxamide 494.0 E: 1.54 F: 1.74 (500 MHz, DMSO-d₆) δ 12.47(s, 1H), 9.30 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 7.3 Hz, 1H), 8.25 (d, J= 7.6 Hz, 1H), 8.22 (s, 1H), 7.97-7.80 (m, 3H), 7.28 (s, 1H), 6.88 (dd,J = 7.6, 2 1 Hz, 1H), 5.26-5.10 (m, 1H), 4.90-4.82 (m, 1H), 4.79-4.71(m, 2H), 4.66 (dd, J = 10.4, 4.9 Hz, 1H), 4.43-4.29 (m, 1H), 3.90 (quin,J = 8.3 Hz, 1H), 2.69-2.55 (m, 2H), 2.45-2.33 (m, 3H), 2.29-2.19 (m,2H), 2.10-2.02 (m, 1H) 434

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin- 1-yl)spiro[3.3]heptan-2-yl)-7-(pyridin-2- yloxy)imidazo [1,2-a]pyridine-3- carboxamide 493.0E: 1.22 F: 1.49 (500 MHz, DMSO-d₆) δ 12.50 (s, 1H), 9.51 (d, J = 7.4 Hz,1H), 8.77 (d, J = 7.4 Hz, 1H), 8.45 (br. s., 1H), 8.25 (d, J = 6.9 Hz,2H), 7.97 (t, J = 7.7 Hz, 1H), 7.94-7.89 (m, 1H), 7.89-7.80 (m, 2H),7.52 (br. s., 1H), 7.32- 7.26 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.17(d, J = 7.3 Hz, 1H), 4.38 (sxt, J = 8.1 Hz, 1H), 3.91 (quin, J = 8.4 Hz,1H), 2.70- 2.62 (m, 1H), 2.61-2.55 (m, 1H), 2.45-2.33 (m, 3H), 2.31-2.20(m, 2H), 2.07 (t, J = 10.0 Hz, 1H) 435

3-isopropyl-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazo [1,5-a]pyridine-1- carboxamide 442.0E: 1.84 F: 1.97 (500 MHz, DMSO-d₆) δ 8.33 (d, J = 7.0 Hz, 1H), 8.25 (d,J = 7.9 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.97-7.80 (m, 4H), 7.05 (t, J= 7.8 Hz, 1H), 6.82 (t, J = 6.9 Hz, 1H), 4.45-4.33 (m, 1H), 3.90 (t, J =8.4 Hz, 1H), 3.53-3.47 (m, 1H), 2.58 (br. s., 2H), 2.43-2.28 (m, 4H),2.20 (br. s., 1H), 2.17-2.10 (m, 1H), 1.35 (d, J = 6.7 Hz, 6H) 436

7-(2,2- difluoroethoxy)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazo [1,2-a]pyridine-3- carboxamide 480.1E: 1.56 F: 1.79 (500 MHz, DMS0-d₆) δ 12.48 (s, 1H), 9.30 (d, J = 7.6 Hz,1H), 8.55 (d, J = 7.0 Hz, 1H), 8.25 (br. s., 2H), 7.98-7.77 (m, 3H),7.20 (br. s., 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.43 (t, J = 54.0 Hz, 1H),4.46 (t, J = 13.9 Hz, 2H), 4.40-4.30 (m, 1H), 3.90 (t, J = 8.4 Hz, 1H),2.64 (br. s., 1H), 2.57 (br. s., 1H), 2.45-2.32 (m, 3H), 2.29-2.18 (m,2H), 2.11-2.00 (m, 1H) 437

7-isopropoxy-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)imidazo [1,2-a]pyridine-3- carboxamide 458.3E: 1.36 F: 1.57 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.23 (d, J = 7.6 Hz,1H), 8.47 (d, J = 7.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H),7.96-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.03 (d, J = 2.1 Hz, 1H), 6.75(dd, J = 7.6, 2.4 Hz, 1H), 4.75 (dt, J = 12.1, 6.1 Hz, 1H), 4.35 (sxt, J= 8.1 Hz, 1H), 3.90 (quin, J = 8.4 Hz, 1H), 2.66-2.60 (m, 1H), 2.59-2.55(m, 1H), 2.42-2.32 (m, 3H), 2.27-2.17 (m, 2H), 2.04 (t, J = 10.1 Hz,1H), 1.30 (d, J = 6.0 Hz, 6H) 438

4-morpholino-N-((aR)- 6-(4-oxo-3,4- dihydrophthalazin-1-yl)spiro[3.3]heptan- 2-yl)pyrazolo[1,5-a] pyridine-3- carboxamide485.2 E: 1.23 F: 1.41 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.70 (d, J =6.4 Hz, 1H), 8.49 (d, J = 6.7 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.23(s, 1H), 7.95-7.79 (m, 3H), 7.08-7.01 (m, 1H), 7.00-6.92 (m, 1H),4.36-4.24 (m, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 3.78 (d, J = 4.0 Hz.4H), 2.96 (br. s., 4H), 2.71 (t, J = 11.3 Hz, 1H), 2.59 (t, J = 8.1 Hz,1H), 2.45-2.38 (m, 1H), 2.37-2.21 (m, 4H), 2.06 (t, J = 9.9 Hz, 1H). 471

7-((4,4- difluorocyclohexyl) oxy-N-((aR)-6-(4- oxo-3,4-dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazo[1,2-a]pyridine-3- carboxamide, TFA 534.4 A: 5.67 B: 8.51 (400 MHz, DMSO-d₆) δ12.47 (s, 1H), 9.45 (d, J = 7.7 Hz, 1H), 8.86 (J = 7.5 Hz, 1H), 8.52 (s,1H), 8.26 (d, J = 7.9 Hz, 1H), 7.97-7.75 (m, 3H), 7.43 (d, J = 2.4 Hz,1H), 7.22 (dd, J = 7.8, 2.3 Hz, 1H), 4.92 (br. s., 1H), 4.46-4.30 (m,1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.71-2.63 (m, 1H), 2.62-2.54 (m, 1H),2.44- 2.36 (m, 4H), 2.32-2.22 (m, 2H), 2.11-1.97 (m, 6H), 1.95-1.84 (m,2H)

Example 439:7-(1-ethyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide;TFA salt

To a solution of Example 363 (10 mg, 0.021 mmol) in dioxane (1 mL) wereadded1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.3mg, 0.042 mmol), K₃PO₄ (13.3 mg, 0.063 mmol), water (0.2 mL), andXPhos-Pd-G2 (1.6 mg, 2.1 μmol) at rt. The reaction was stirred under N₂at 100° C., for 2 h. The reaction was cooled to rt, and the solvent wasremoved. Purification by reverse phase chromatography provided Example439 (7.9 mg, 62%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.43 (d,J=7.3 Hz, 1H), 8.70 (d, J=7.3 Hz, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 8.26(d, J=7.9 Hz, 1H), 8.14 (s, 1H), 7.97-7.80 (m, 4H), 7.53 (d, J=7.0 Hz,1H), 4.38 (sxt, J=8.1 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.91 (quin, J=8.5Hz, 1H), 2.70-2.62 (m, 1H), 2.58 (t, J=7.9 Hz, 1H), 2.45-2.35 (m, 3H),2.32-2.22 (m, 2H), 2.08 (t, J=10.1 Hz, 1H), 1.42 (t, J=7.3 Hz, 3H).LC-MS(ESI) m/z: 494.1 [M+H]⁺. Analytical HPLC RT=1.42 min (Method E),1.63 min (Method F).

Examples in Table 24 were prepared by following a similar Suzuki-Miyaracoupling reaction procedure to that described in Example 439 using theappropriate halides and boronic acids or esters. Other appropriatepalladium catalysts and ligands could also be used.

TABLE 24 HPLC LCMS Method, Ex. Structure Name [M + H]⁺ RT (min.) ¹H NMR(δ NMR) 440

7-(1-methyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)imidazo[1,2- a]pyridine-3- carboxamide480.3 E: 1.10 F: 1.12 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.38 (d, J =7.2 Hz, 1H), 8.58 (d, J = 7.3 Hz, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.25(d, J = 7.9 Hz, 1H), 8.09 (s, 1H), 7.96-7.79 (m, 4H), 7.39 (d, J = 7.2Hz, 1H), 4.45-4.31 (m, 1H), 3.95-3.89 (m., 1H), 3.88 (s, 3H), 2.65 (br.s., 1H) 2.58 (t, J = 8.0 Hz, 1H), 2.44-2.33 (m, 3H), 2.30-2.20 (m, 2H),2.07 (t, J = 10.0 Hz, 1H) 441

7-(1-isopropyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)imidazo[1,2- a]pyridine-3- carboxamide508.1 E: 1.51 F: 1.72 (500 MHz, DMSO-d₆) δ 9.38 (d, J = 7.0 Hz, 1H),8.56 (d, J = 7.3 Hz, 1H), 8.48 (s. 1H), 8.31 (s, 1H), 8.27 (d, J = 7.9Hz, 1H), 8.10 (s, 1H), 7.98-7.82 (m, 4H), 7.41 (d, J = 7.0 Hz, 1H), 4.54(dt, J = 13.2, 6.4 Hz, 1H), 4.44-4.34 (m, 1H), 3.99-3.86 (m, 1H), 2.67(br. s., 1H), 2.63-2.57 (m, 1H), 2.47-2.35 (m, 3H), 2.33-2.22 (m, 2H),2.09 (t, J = 9.8 Hz, 1H), 1.48 (d, J = 6.7 Hz, 6H) 442

7-(1-(methyl-d3)- 1H-pyrazol-4-yl)- N-((aR)-6-(4-oxo- 3,4-dihydrophthalazin- 1- yl)spiro[3.3]heptan- 2-yl)imidazo[1,2-a]pyridine-3- carboxamide 483.1 E: 1.38 F: 1.55 (500 MHz, DMSO-d₆) δ12.48 (s, 1H), 9.43 (d, J = 7.0 Hz, 1H), 8.73 (d, J = 7.3 Hz, 1H),8.49-8.37 (m, 2H), 8.25 (d, J = 7.9 Hz, 1H), 8.13 (s, 1H), 7.97-7.80 (m,4H), 7.53 (d, J = 7.0 Hz, 1H), 4.38 (sxt, J = 8.0 Hz, 1H), 3.91 (quin, J= 8.4 Hz, 1H), 2.65 (d, J = 10.7 Hz, 1H), 2.61-2.55 (m, 1H), 2.45-2.33(m, 3H), 2.31-2.20 (m, 2H), 2.07 (t, J = 9.9 Hz, 1H) 443

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin- 1- yl)spiro[3.3]heptan-2-yl)-7-(1- (tetrahydro-2H- pyran-4-yl)-1H- pyrazol-4- yl)imidazo[l,2-a]pyridine-3- carboxamide 550.1 E: 1.43 F: 1.63 (500 MHz, DMSO-d₆) δ12.48 (s, 1H), 9.36 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 7.3 Hz:, 1H), 8.50(s, 1H), 8.30 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.96-7.80(m, 4H), 7.40 (d, J = 7.3 Hz, 1H), 4.47-4.32 (m, 2H), 3.97 (d, J = 9.2Hz, 2H), 3.93-3.86 (m, 1H), 3.53-3.42 (m, 2H), 2.65 (br. s., 1H), 2.58(t, J = 8.4 Hz, 1H), 2.46-2.33 (m, 3H), 2.30-2.20 (m, 2H), 2.11-1.92 (m,5H) 444

7-(1-isopropyl-3- (trifluoromethyl)- 1H-pyrazol-4-yl)- N-((aR)-6-(4-oxo-3,4- dihydrophatalazin- 1- yl)spiro[3.3]heptan- 2-yl)imidazo[1,2-a]pyridine-3- carboxamide 576.1 E: 1.76 F: 2.03 (500 MHz, DMSO-d₆) δ12.48 (s, 1H), 9.45 (d, J = 7.3 Hz, 1H), 8.62 (d, J = 7.3 Hz, 1H), 8.52(s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.96-7.80 (m, 3H), 7.70(s, 1H), 7.20 (d, J = 7.3 Hz, 1H), 4.64 (dt, J = 13.4, 6.6 Hz, 1H), 4.40(sxt, J = 8.2 Hz, 1H), 3.91 (quin, J = 8.5 Hz, 1H), 2.70-2.62 (m, 1H),2.62-2.55 (m, J = 7.9, 7.9 Hz, 1H), 2.46-2.35 (m, 3H), 2.32-2.22 (m,2H), 2.09 (t, J = 9.8 Hz, 1H), 1.50 (d, J = 6.7 Hz, 6H) 445

4-(1-ethyl-1H- pyrazol-4-yl)-3- fluoro-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin- 1- yl)spiro[3.3]heptan- 2-yl)benzamide 472.1 E: 1.72F: 1.77 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.64 (d, J = 7.3 Hz, 1H),8.32-8.18 (m, 2H), 7.97 (s, 1H), 7.94-7.89 (m, 1H), 7.89-7.77 (m, 3H),7.75-7.67 (m, 2H), 4.42-4.29 (m, 1H), 4.19 (q, J = 7.3 Hz, 2H), 3.90(quin, J = 8.4 Hz, 1H), 2.66-2.53 (m, 2H), 2.44-2.31 (m, 3H), 2.28-2.18(m, 2H), 2.07 (t, J = 9.9 Hz, 1H), 1.40 (t, J = 7.2 Hz, 3H) 446

3-fluoro-4-(1- isopropyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4-dihydrophthalazin- 1- yl)spiro[3.3]heptan- 2-yl)benzainide 486.1 E: 1.62F: 1.87 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.64 (d., J = 7.3 Hz, 1H),8.31-8.20 (m, 2H), 7.96 (s, 1H), 7.94-7.78 (m, 4H), 7.75-7.66 (m, 2H),4.56 (dt, J = 13.2, 6.7 Hz, 1H), 4.40-4.28 (m, 1H), 3.95-3.83 (m, 1H),2.67-2.55 (m, 2H), 2.45-2.32 (m, 3H), 2.28-2.17 (m, 2H), 2.07 (t, J =10.1 Hz, 1H) 1.45 (d, J = 6.7 Hz, 6H) 447

3-fluoro-4-(1- methyl-5- (trifluoromethyl)- 1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo- 3,4- dihydropinhalazin- 1- yl)spiro[3.3]heptan-2-yl)benzamide 526.1 E: 1.84 F: 2.15 (500 MHz, DMSO-d₆) δ 12.49 (s, 1H),8.74 (d, J = 7.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.19 (s, 1H),7.98-7.82 (m, 3H), 7.79-7.71 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H),4.42-4.30 (m, 1H), 4.00 (s, 3H), 3.92 (quin, J = 8.5 Hz, 1H), 2.68-2.57(m, 2H), 2.46-2.33 (m, 3H), 2.26 (t, J = 9.8 Hz, 2H), 2.09 (t, J = 9.9Hz, 1H) 448

4-(1-cyclopropyl- 1H-pyrazol-4-yl)-3- fluoro-N-((aR)-6- (4-oxo-3,4-dihydrophthalazin- 1- yl)spiro[3.3]heptan- 2-yl)benzamide 484.1 E: 1.76F: 1.82 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.64 (d, J = 7.3 Hz, 1H),8.28 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.89-7.77 (m, 3H), 7.73-7.65 (m, 2H), 4.34 (sxt, J = 7.9 Hz,1H), 3.97-3.83 (m, J = 8.5, 8.5 Hz, 1H, 3.79 (br. s., 1H), 2.66-2.55 (m,2H), 2.44-2.33 (m, 3H), 2.28-2.19 (m, 2H), 2.11-2.02 (m, 1H), 1.12-1.06(m, 2H), 1.02-0.96 (m, J = 5.5 Hz, 2H) 449

3-fluoro-N-((aR)-6- (4-oxo-3,4- dihydrophthalazin- 1-yl)spiro[3,3]heptan- 2-yl)-4-(1- (tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4- yl)benzainide 528.0 E: 1.64 F: 1.98 (500 MHz, DMSO-d₆) δ12.47 (br s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.32 (br. s., 1H), 8.25 (d,J = 7.3 Hz, 1H), 7.99 (br. s., 1H), 7.93-7.79 (m, 4H), 7.76-7.69 (m, 2H)4.48 (br. s., 1H) 4.35 (d, J = 7.0 Hz, 1H), 3.98 (d, J = 10.7 Hz, 2H),3.90 (br. s.. 2H), 3.49 (d, J = 13.4 Hz, 1H), 2.62 (br. s., 2H), 2.39(d, J = 13.7 Hz, 3H), 2.24 (d, J = 8.2 Hz, 2H), 2.09 (d, J = 9.8 Hz,1H), 2.00 (br. s., 4H) 450

5-(1-methyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)picolinamide 441.0 E: 1.45 F: 1.52 (500MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.85 (s, 1H), 8.80 (d, J = 7.9 Hz, 1H),8.37 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.06(s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.94-7.80 (m, 3H), 4.46-4.28 (m, 1H),3.90 (s, 3H), 3.95-3.84 (m, 1H), 2.58 (d, J = 9.2 Hz, 2H), 2.45-2.30 (m,4H), 2.26-2.12 (m, 2H) 451

4-(1-methyl-1H- pyrazol-4-yl)-N- ((aR)-6-(4-oxo-3,4- dihydrophthalazin-1- yl)spiro[3.3]heptan- 2-yl)benzamide 440.3 E: 1.38 F: 1.33 (500 MHz,DMSO-d₆) δ 12.49 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 7.8 Hz,1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H),7.83 (d, J = 7.7 Hz, 3H), 7.64 (d, 8.2 Hz, 2H), 4.44-4.27 (m, 1H),3.95-3.88 (m, 1H), 3.86 (s, 3H), 2.68-2.55 (m, 2H), 2.44-2.31 (m, 3H),2.28-2.17 (m, 2H), 2.07 (t, J = 10.0 Hz, 1H) 452

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin- 1- yl)spiro[3.3]heptan-2-yl)-7-(pyridia-3- yl)imidazo[1,2- a]pyridiae-3- carboxamide 477.1 E:1.39 F: 1.71 (500 MHz, DMSO-d₆) δ 12.48 (s, 1H), 9.51 (d, J = 7.3 Hz,1H), 9.09 (s, 1H), 8.69-8.59 (m, 2H), 8.41 (s, 1H), 8.31-8.22 (m, 2H),8.14 (s, 1H), 7.97-7.80 (m, 3H), 7.61-7.50 (m, 2H), 4.48-4.34 (m, 1H),3.98-3.85 (m, 1H), 2.67 (br. s., 1H), 2.63-2.55 (m, 1H), 2.45-2.34 (m,3H), 2.32-2.23 (m, 2H), 2.09 (t, J = 10.1 Hz, 1H) 453

N-((aR)-6-(4-oxo- 3,4- dihydrophthalazin- 1- yl)spiro[3.3]heptan-2-yl)-7-(pyridin-3- yl)imidazo[1,2- a]pyridine-2- carboxamide 477.0 E:1.40 F: 1.68 (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.05 (s, 1H), 8.95 (s,1H), 8.63 (d, J = 4.3 Hz, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.35 (s, 1H),8.25 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.95-7.81 (m, 3H),7.79-7.69 (m, 2H), 7.59-7.52 (m, 1H), 4.46-4.32 (m, 1H), 3.97-3.81 (m, J= 8.4, 8.4 Hz, 1H), 2.65-2.53 (m, 2H), 2.44-2.30 (m, 4H), 2.25-2.13 (m,2H) 454

7-(2-methylthiazol- 5-yl)-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazo[1,2- a]pyridine-2- carboxamide 497.2E: 1.22 F: 1.45 (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.90 (s, 1H), 8.52(d, J = 8.1 Hz, 1H), 8.32 (s, 1H), 8.25 (d, J = 7.0 Hz, 1H), 8.08 (s,1H), 7.95-7.81 (m, 3H), 7.70-7.62 (m, 2H), 4.38 (sxt, J = 8.0 Hz, 1H),3.89 (quin, J = 8.4 Hz, 1H), 2.71 (s, 3H), 2.62-2.55 (m, 2H), 2.42-2.32(m, 5H), 2.21-2.16 (m, 1H) 455

7-(2-methylthiazol- 5-yl)-N-((aR)-6-(4- oxo-3,4- dihydrophthalazin- 1-yl)spiro[3.3]heptan- 2-yl)imidazo[1,2- a]pyridine-3- carboxamide 497.3A: 4.78 B: 6.80 (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.49 (d, J = 7.3 Hz,1H), 8.77 (d, J = 7.5 Hz, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 8.26 (d, J =7.9 Hz, 1H), 7.98 (s, 1H), 7.95-7.80 (m, 3H), 7.61 (dd, J = 7.4, 1.9 Hz,1H), 4.40 (sxt, J = 8.1. Hz, 1H), 3.92 (quin, J = 8.5 Hz, 1H), 2.75-2.70(m, 3H), 2.69-2.63 (m, 1H), 2.62-2.55 (m, 1H), 2.44-2.36 (m, 3H),2.31-2.22 (m, 2H), 2.14-2.04 (m, 1H)

Example 457:4-((aR)-6-(1-oxoisoindolin-2-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

To a solution of Intermediate 2 (15 mg, 0.051 mmol) in MeOH (1 mL) wereadded methyl 2-formylbenzoate (25 mg, 0.15 mmol) and NaBH(OAc)₃ (33 mg,0.15 mmol) at rt. The reaction was stirred under N₂ at rt for 1 h. Itwas heated then at 50° C., for another 1 h. The reaction was quenched byadding one drop of TFA, and then was diluted with DMF. Purification byreverse phase chromatography provided Example 457 (4.0 mg, 21%).LC-MS(ESI) m/z: 372.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.50 (s, 1H),8.26 (d, J=7.8 Hz, 1H), 7.98-7.78 (m, 3H), 7.66 (d, J=7.5 Hz, 1H), 7.59(d, J=3.7 Hz, 2H), 7.48 (d, J=3.5 Hz, 1H), 4.69 (t, J=8.4 Hz, 1H),4.61-4.46 (m, 2H), 4.02-3.82 (m, 1H), 2.68-2.53 (m, 2H), 2.48-2.35 (m,4H), 2.34-2.26 (m, 1H), 2.18 (d, J=4.7 Hz, 1H). Analytical HPLC RT=1.45min (Method E), 1.46 min (Method F).

Example 458:4-((aR)-6-((S)-4-benzyl-2-oxoimidazolidin-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

Example 458A: tert-butyl((S)-1-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)amino)-3-phenylpropan-2-yl)carbamate

To a solution of Intermediate 2 (20 mg, 0.069 mmol) in McOH (1 mL) wereadded (S)-tert-butyl (1-oxo-3-phenylpropan-2-yl)carbamate (18.8 mg,0.075 mmol) and NaBH(OAc)₃ (44 mg, 0.21 mmol) at it. The reaction wasstirred under N₂ at rt for 3 h. The solvent was removed to give a whitesolid of crude product, which was used in the next step. LC-MS(ESI) m/z:489.1 [M+H]⁺.

Example 458

To a solution of Example 458A (33.7 mg, 0.069 mmol) in DCM (2 mL) wasadded TFA (1.0 mL) at rt. The reaction was stirred at rt for 30 min andthe solvent was removed. To the residue were added DMF (1 mL), DIEA (0.1mL) and then CDI (11 mg, 0.069 mmol) at rt. The reaction was stirredunder N₂ at 60° C., for 1 h. Purification by reverse phasechromatography provided Example 458 (2.2 mg, 8%). LC-MS(ESI) m/z: 415.3[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.24 (d, J=7.7 Hz,1H), 7.90 (d, J=7.6 Hz, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.36-7.26 (m, 2H),7.23 (d, J=7.4 Hz, 3H), 6.51 (s, 1H), 4.10 (t, J=8.5 Hz, 1H), 3.93-3.71(m, 2H), 3.30 (t, J=8.5 Hz, 1H), 3.04 (t, J=7.4 Hz, 1H), 2.81 (d, J=9.0Hz, 1H), 2.69-2.61 (m, 1H), 2.39-2.19 (m, 4H), 2.18-2.08 (m, 1H), 2.01(t, J=9.8 Hz, 1H), 1.90 (s, 2H). Analytical HPLC RT=1.68 min (Method E).

Example 459:4-((aR)-6-((R)-4-benzyl-2-oxoimidazolidin-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

Example 459 was prepared by following the same procedure as described inthe Example 458 by replacing (S)-tert-butyl(1-oxo-3-phenylpropan-2-yl)carbamate with (R)-tert-butyl(1-oxo-3-phenylpropan-2-yl)carbamate. LC-MS(ESI) m/z: 415.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.24 (d, J=7.9 Hz, 1H),7.93-7.87 (m, 1H), 7.86-7.78 (m, 2H), 7.33-7.26 (m, 2H), 7.22 (d, J=7.3Hz, 4H), 4.17-4.06 (m, J=8.1, 8.1 Hz, 1H), 3.93-3.73 (m, 2H), 3.39-3.27(m, 2H), 3.08-2.98 (m, 1H), 2.81 (dd, J=13.4, 4.9 Hz, 1H), 2.64 (dd,J=13.6, 7.8 Hz, 1H), 2.38-2.24 (m, 4H), 2.21-2.15 (m, 1H), 1.99 (t,J=10.4 Hz, 1H), 1.86 (br, s., 1H). Analytical HPLC RT=1.69 min (MethodE), 1.74 min (Method F).

Example 460:4-((aR)-6-((2-nitrophenyl)amino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

To a solution of Intermediate 2 (20 mg, 0.069 mmol) in DMF (1 mL) wereadded 1-fluoro-2-nitrobenzene (11 mg, 0.075 mmol) and DIEA (0.060 mL,0.34 mmol) at rt. The reaction was stirred under N₂ at 50° C., for 3 h.The solvent was removed. Purification by normal phase chromatographyprovided Example 460 (24 mg, 91%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) 12.46 (s, 1H), 8.28-8.19 (m, 1H), 8.07 (dd, J=8.6, 1.5 Hz, 1H),7.99 (d, J=5.7 Hz, 1H), 7.95-7.89 (m, 1H), 7.88-7.79 (m, 2H), 7.54 (td,J=7.8, 1.5 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.72 (ddd, J=8.4, 7.0, 1.1Hz, 1H), 4.13-4.00 (m, 1H), 3.92 (quin, J=8.4 Hz, 1H), 2.84 (ddd,J=11.1, 6.7, 4.8 Hz, 1H), 2.64-2.56 (m, 1H), 2.47-2.36 (m, 4H), 2.19(dd, J=10.8, 7.9 Hz, 1H), 1.98 (dd, J=11.1, 7.8 Hz, 1H). LC-MS(ESI) m/z:377.1 [M+H]⁺. Analytical HPLC RT=9.71 min (Method A), 10.64 min (MethodB).

Example 461:4-((aR)-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

Example 461A:4-((aR)-6-((2-aminophenyl)amino)spiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

To a flask containing Example 460 (22 mg, 0.058 mmol) were addedcatalytic amount of 10% Pd/C and MeOH (5 mL). The reaction was stirredunder a hydrogen balloon at rt for 2 h. The catalyst was filtered, andthe solvent was removed from filtrate to give a white solid (19.5 mg,96%). LC-MS(ESI) m/z: 347.1 [M+H]⁺.

Example 461

To a solution of Example 461A (19 mg, 0.055 mmol) in DMF (1 mL) wereadded CDI (8.9 mg, 0.055 mmol) and DIEA (0.03 mL, 0.17 mmol) at rt. Thereaction was stirred under N₂ at it for 1 h. Purification by reversephase chromatography provided Example 461 (7.4 mg, 36%). ¹H NMR (500MHz, DMSO-d₆) δ 12.48 (s, 1H), 10.82 (s, 1H), 8.26 (d, J=7.9 Hz, 1H),7.96-7.87 (m, 2H), 7.87-7.80 (m, 1H), 7.23 (d, J=7.0 Hz, 1H), 7.06-6.92(m, 3H), 4.73 (quin, J=8.9 Hz, 1H), 4.01-3.85 (m, 1H), 2.98 (t, J=10.2Hz, 1H), 2.81 (t, J=10.5 Hz, 1H), 2.72-2.61 (m, 2H), 2.53-2.41 (m, 3H),2.32-2.22 (m, 1H). LC-MS(ESI) m/z: 373.2 [M+H]⁺. Analytical HPLC RT=1.55min (Method E), 1.52 min (Method F).

Example 462:4-cyclopropyl-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

A vial charged with Example 304 (15 mg, 0.031 mmol), cyclopropylboronicacid (10.8 mg, 0.13 mmol), Pd(OAc)₂ (0.70 mg, 3.1 μmol) and K₃PO₄ (20mg, 0.094 mmol) was degassed and purged with argon, and then toluene(2.0 mL) and H₂O (0.2 mL) were added. The mixture was degassed again andthen tricyclohexylphosphonium tetrafluoroborate (2.3 mg, 6.3 μmol) wasadded at rt. The reaction was heated in a sealed vial at 100° C., for 3h. The solvent was removed. Purification by reverse phase chromatographyprovided Example 462 (2.2 mg, 15%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.49(s, 1H), 8.55 (d, J=6.5 Hz, 1H), 8.48 (d, J=7.3 Hz, 1H), 8.25 (d, J=7.7Hz, 1H), 8.22 (s, 1H), 7.98-7.75 (m, 3H), 6.97-6.85 (m, 2H), 4.32 (sxt,J=8.0 Hz, 1H), 3.89 (quin, J=8.4 Hz, 1H), 2.89 (d, J=7.8 Hz, 1H),2.67-2.58 (m, 1H), 2.58-2.54 (m, 1H), 2.44-2.29 (m, 3H), 2.27-2.13 (m,2H), 2.01 (t, J=10.0 Hz, 1H), 0.88 (d, J=8.4 Hz, 2H), 0.67 (d, J=4.5 Hz,2H). LC-MS(ESI) m/z: 440.2 [M+H]⁺. Analytical HPLC RT=1.42 min (MethodF).

Example 463:3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)picolinamide

To a solution of Intermediate 2 (20 mg, 0.078 mmol) in DMF (1 mL) wereadded 5-bromo-3-fluoropicolinic acid (17.2 mg, 0.078 mmol), HATU (32.8mg, 0.086 mmol) and DIEA (0.068 mL, 0.39 mmol) at rt. The reaction wasstirred under N₂ at rt for 1 h. To the reaction were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(24.5 mg, 0.12 mmol), K₃PO₄ (50 mg, 0.24 mmol), water (0.2 mL), andXPhos-G2-Pd-preCat (6.2 mg, 7.8 μmol). The reaction was heated at 90°C., for 2 h, and then it was cooled to rt. It was filtered. Purificationby reverse phase chromatography provided Example 463 (7.4 mg, 21%). ¹HNMR (500 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.73 (d, J=7.9 Hz, 1H), 8.71(br, s., 1H), 8.42 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 8.11 (s, 1H), 8.04(d, J=12.2 Hz, 1H), 7.95-7.80 (m, 3H), 4.40-4.26 (m, 1H), 3.89 (s, 3H),3.95-3.82 (m, 1H), 2.57 (d, J=9.5 Hz, 2H), 2.45-2.33 (m, 3H), 2.32-2.25(m, 1H), 2.22 (br, s., 1H), 2.15-2.04 (m, 1H). LC-MS(ESI) m/z: 459.1[M+H]⁺. Analytical HPLC RT=1.44 min (Method E), 1.48 min (Method F).

Example 464: 6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-ylisoindoline-2-carboxylate

Example 464A: 4-(6-hydroxyspiro[3.3]heptan-2-yl)phthalazin-1(2H)-one

To a solution of Intermediate 2 (50 mg, 0.17 mmol) in dioxane (1 mL) andH₂O (1 mL) were addeddichloro[(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II)(6.8 mg, 8.6 μmol) and TEA (1 drop) at rt. The reaction was heated in asealed vial at 120° C., for 12 h. The solvent was removed. The crudeproduct was purified by reverse phase chromatography to give Example464A (10 mg, 23%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.35 (dd,J=7.8, 1.0 Hz, 1H), 7.83-7.78 (m, 1H), 7.77-7.71 (m, 1H), 7.69 (d,0.1-8.1 Hz, 1H), 4.13 (quin, J=7.4 Hz, 1H), 3.80 (quin, J=8.5 Hz, 1H),2.62-2.54 (m, 1H), 2.47-2.31 (m, 4H), 2.25 (dt, J=11.7, 6.1 Hz, 1H),2.02 (dd, J=11.0, 7.7 Hz, 1H), 1.86 (dd, J=11.4, 7.7 Hz, 1H). LC-MS(ESI)m/z: 257.0 [M+H]⁺.

Example 464

To a solution of Example 464A (10 mg, 0.039 mmol) in THF (2 mL) wasadded phosgene (129 mg, 0.20 mmol) at rt. The reaction was stirred at rtovernight. The solvent was removed. To the residue were added DCM (2mL), isoindoline (14 mg, 0.12 mmol) and TEA at 0° C. The reaction wasstirred under N₂ at rt for 2 h. The solvent was removed. The crudeproduct was purified by reverse phase chromatography to provide Example464 (2.5 mg, 16%) as a light tan solid. ¹H NMR (400 MHz, CD₃OD) δ 8.36(d, J=7.9 Hz, 1H), 7.96-7.87 (m, 2H), 7.87-7.80 (m, 1H), 7.35-7.25 (m,4H), 4.96 (quin, J=7.1 Hz, 1H), 4.72 (s, 2H), 4.68 (s, 2H), 3.96 (quin,J=8.3 Hz, 1H), 2.82-2.72 (m, 1H), 2.62-2.48 (m, 4H), 2.42 (dt, J=11.9,5.9 Hz, 1H), 2.31 (dd, J=11.4, 7.3 Hz, 1H), 2.13 (dd, J=11.8, 7.4 Hz,1H). LC-MS(ESI) m/z: 402.2 [M+H]⁺. Analytical HPLC RT=8.75 min (MethodA), 9.65 min (Method B).

Example 465:7-(methylsulfonyl)-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carboxamide

To a solution of Example 414 (15 mg, 0.027 mmol) in DCM (3 mL) wereadded mCPBA (23 mg, 0.13 mmol) at rt. The reaction was stirred under N₂at it for 2 h. The solvent was removed. Purification by reverse phasechromatography provided Example 465 (3.1 mg, 18%). ¹H NMR (500 MHz,DMSO-d₆) δ 12.50 (s, 1H), 9.61 (d, J=7.3 Hz, 1H), 8.87 (d, J=7.3 Hz,1H), 8.54 (br, s., 1H), 8.30-8.16 (m, 2H), 7.95-7.89 (m, 1H), 7.89-7.81(m, 2H), 7.54 (d, J=7.1 Hz, 1H), 4.39 (sxt, J=8.1 Hz, 1H), 3.95-3.84 (m,1H), 3.32 (s, 3H), 2.65 (br, s., 1H), 2.58 (hr, s., 1H), 2.43-2.33 (m,3H), 2.29-2.21 (m, 2H), 2.12-2.02 (m, 1H). LC-MS(ESI) m/z: 478.1 [M+H]⁺.Analytical HPLC RT=1.18 min (Method E), 1.23 min (Method F).

Example 469:2-methyl-2-((3-(((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)carbamoyl)pyrazolo[1,5-a]pyridin-6-yl)oxy)propanoicacid

To a suspension of Intermediate 77 (17.3 mg, 0.054 mmol) andIntermediate 2, HCl (13.7 mg, 0.047 mmol) in DMF (5 mL), were added HATU(19.6 mg, 0.052 mmol) and DIEA (0.025 mL, 0.141 mmol). The mixture wasstirred at it for 1 h, then was diluted with EtOAc. The organic phasewas washed with H₂O (2×) and brine, dried (Na₂SO₄) and concentrated. Theresidue was dissolved in TFA (1 mL) with a drop of water. The mixturewas stirred at rt for 45 min, then was concentrated. The product waspurified by preparative HPLC to afford Example 469 (24 mg, 100% yield).¹H NMR (500 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H),8.23 (dd, J=14.2, 7.8 Hz, 2H), 8.05 (d, J=9.8 Hz, 1H), 7.91-7.85 (m,1H), 7.85-7.76 (m, 2H), 7.23 (d, J=9.5 Hz, 1H), 4.38-4.26 (m, 1H), 3.86(quin, J=8.4 Hz, 1H), 2.64-2.52 (m, 2H), 2.41-2.29 (m, 3H), 2.24-2.11(m, 2H), 2.00 (t, J=10.1 Hz, 1H), 1.48 (s, 6H), LC-MS(ESI) m/z: 424.4[M+H]⁺. Analytical HPLC RT=1.48 min (Method E), 1.163 min (Method F).

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: Ring A is a 5- to 9-membered bicyclic spirocarbocycle; Ring B is selected from a C₅₋₆ carbocycle and a 5- to6-membered heterocycle; ----- is an optional bond; M is absent orselected from N and CR¹⁰; L is selected from —(CR⁴R⁴)₀₋₁—,—(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—; R¹ is selected fromNR⁴R⁴, OR⁵, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and —(CR⁴R⁴)_(n)-4- to15-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle,and heterocycle are substituted with 1-4 R⁷; R², at each occurrence, isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl), —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl),—CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —C(═NH)NH₂, a carbocycle, and a heterocycle, wherein saidalkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R³, at each occurrence, is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl),—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂,—C(═NH)NH₂, a carbocycle, and a heterocycle, wherein said alkyl, alkoxy,alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁴, at each occurrence, is independently selected from H, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹, R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and—(CR⁶R⁶)_(n)-4- to 10-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein saidalkyl, carbocycle and heterocycle are substituted with 1-4 R⁷;alternatively, R⁵and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered substituted with 1-4R⁷; R⁶, at each occurrence, is independently selected from H, C₁₋₄alkyl, CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl),CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and a heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; alternatively, R¹ and R⁶ are taken togetherwith the nitrogen atom to which they are attached to form a heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p) and substituted with 1-4 R⁷; R⁷, at each occurrence, isindependently selected from H, ═O, NO₂, halogen, C₁₋₇ alkyl, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, CN, OH, CHF₂, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCOH,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁸, at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,—(CH₂)_(n)—C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)carbocycle,—(CH₂)_(n)—C(O)heterocycle, —(CH 2)_(n)—C(O)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)C(O) C₁₋₄alkyl, —(CH₂)_(n)—C(O)OC₁₋₄alkyl,—(CH₂)_(n)—C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)O-carbocycle,—(CH₂)_(n)—C(O)O-heterocycle, —(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n)SO₂carbocycle, —(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; alternatively,R⁸ and R⁸ are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle substituted with 0-4R⁹; R⁹, at each occurrence, is independently selected from halogen, OH,═O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰R¹⁰)_(n)carbocycle, —O(CHR¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl;R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c); alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b); R^(b), at each occurrence, is independentlyselected from ═O, OH, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄alkyl, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl),CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl),—R^(c), COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxyare substituted with R^(d); R^(c), at each occurrence, is independentlyselected from —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-5- to 6-membered heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); n, at each occurrence, is independently selected from0, 1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 2. The compound of claim 1, having Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein:

is selected from

M is selected from N and CR¹⁰; L is selected from —(CR⁴R⁴)₀₋₁—,—(CR⁴R⁴)₀₋₁C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—; R¹ is selected fromNR⁵R⁵, OR⁵, —(CR⁴R⁴)_(n)C₃₋₁₀ carbocycle and —(CR⁴R⁴)_(n)-4- to15-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle,and heterocycle are substituted with 1-4 R⁷; R², at each occurrence, isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁-(haloalkyl, —OH, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl),—CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —C(═NH)NH₂, a carbocycle, and a heterocycle, wherein saidalkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R³, at each occurrence, is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl),—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂,—C(═NH)NH₂, a carbocycle, and a heterocycle, wherein said alkyl, alkoxy,alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁴, at each occurrence, is independently selected from H, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, a carbocycle, and a heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and—(CR⁶R⁶)_(n)-4- to 10-membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, NR, O, and S(O)_(p), wherein saidalkyl, carbocycle and heterocycle are substituted with 1-4 R⁷;alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a 4- to 15-membered heterocyclesubstituted with 1-4 R⁷; R⁶, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, CH₂NH₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, CH₂OH,CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄ alkyl), a carbocycle, and aheterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; alternatively, R¹ and R⁶ aretaken together with the nitrogen atom to which they are attached to forma heterocycle comprising carbon atoms and 1-4 heteroatoms selected fromN, NR⁸, O, and S(O)_(p) and substituted with 1-4 R⁷; R⁷, at eachoccurrence, is independently selected from H, ═O, NO₂, halogen, C₁₋₆alkyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH)_(n)—NR⁸R⁸, —NHCOH,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkoxyl, a carbocycle, and a heterocycle aresubstituted with 0-4 R⁹; R⁸, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,—(CH₂)_(n)—C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)carbocycle,—(CH₂)_(n)—C(O)heterocycle, —(CH 2)_(n)—C(O)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)OC₁₋₄alkyl,—(CH₂)_(n)—C(O)C₁₋₄alkyl, —(CH₂)_(n)—C(O)O-carbocycle,—(CH₂)_(n)—C(O)O-heterocycle, —(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n)SO₂carbocycle, —(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; alternatively,R⁸ and R⁸ are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle substituted with 0-4R⁹; R⁹, at each occurrence, is independently selected from halogen, OH,═O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰R¹⁰)carbocycle, —O(CHR¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl;R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c): alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b); R^(b), at each occurrence, is independentlyselected from ═O, OH, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄alkyl, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl),CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl),—R^(c), COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl and alkoxyare substituted with R^(d); R^(c), at each occurrence, is independentlyselected from —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-5- to 6-membered heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); n, at each occurrence, is independently selected from0, 1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 3. The compound of claim 2, having Formula (III):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: M is selected from N and CR¹⁰; R¹ is selected fromNR⁵R⁵, OR⁵, —(CH₂)_(n)—C₃₋₁₀ carbocycle, and —(CH₂)_(n)-5- to10-membered heterocycle, wherein said carbocycle and heterocycle aresubstituted with 1-4 R⁷; R³, at each occurrence, is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, and —NH₂; R⁵, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷; alternatively, R⁵ and R⁵ are taken togetherwith the nitrogen atom to which they are attached to form a 4- to10-membered heterocycle substituted with 1-4 R⁷; R⁶, at each occurrence,is independently selected from H and C₁₋₄ alkyl; R⁷, at each occurrence,is independently selected from H, ═O, NO₂, halogen, C₁₋₆ alkyl, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCOH, —NHCO(C₁₋₄ alkyl), —NHCOCF₃,—NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl),—S(O)_(p)(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,—SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, —NHCO-carbocycle,—NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; R⁸, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)—C(O)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)C(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹; R⁹, at each occurrence, is independently selected fromhalogen, OH, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰)_(n)carbocycle, —O(CHR¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl;R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R,and CONHR^(c): alternatively, R^(a) and R^(a) are taken together withthe nitrogen atom to which they are attached to form a 4- to 10-memberedheterocycle, wherein said alkyl, alkylene, and heterocycle aresubstituted with 0-4 R^(b); R^(b), at each occurrence, is independentlyselected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OC(O)C₁₋₄alkyl, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl),CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c), wherein said alkyl andalkoxy are substituted with R^(d); R^(c), at each occurrence, isindependently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halogen, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), and aheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; andp, at each occurrence, is independently selected from 0, 1, and
 2. 4.The compound of claim 3, having Formula (IV):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl),—NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹; alternatively, R⁸ and R⁸ are taken together with the nitrogen atomto which they are attached to form a 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —(CH₂)_(n)NHCO(C₁₋₄ alkyl),—O(CH₂)_(n)heterocycle, —O(CH₂)₂₋₄NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b); R^(a), at each occurrence,is independently selected from H and C₁₋₄ alkyl; alternatively, R^(a)and R^(a) are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle, wherein said alkyl,alkylene, and heterocycle are substituted with 0-4 R^(b); and R^(b), ateach occurrence, is independently selected from ═O, halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, and —NHCO₂(C₁₋₄ alkyl). 5.The compound of claim 4 or a stereoisomer, a tautomer, apharmaceutically-acceptable salt thereof, wherein: R¹ is selected from

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, —NR⁸R⁸, C₃₋₆ cycloalkyl, phenyl, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-heterocycle, wherein said alkyl, cycloalkyl, phenyl, andheterocycle are substituted with 0-4 R⁹; alternatively, R⁸ and R⁸ aretaken together with the nitrogen atom to which they are attached to forma heterocycle selected from

R⁹, at each occurrence, is independently selected from F, Cl, OH, CN,C₁₋₄ alkyl, C₁₋₄ alkoxy, —(CH₂)_(n)NR^(a)R^(a), and a 4- to 10-memberedheterocycle, wherein said alkyl, alkoxyl, and heterocycle aresubstituted with 0-4 R^(b); R^(a), at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃,CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), and C₁₋₄alkylene-CO₂(C₁₋₄ alkyl); and R^(b), at each occurrence, isindependently selected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂,NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, and —NHCO₂(C₁₋₄alkyl).
 6. The compound of claim 3 or a stereoisomer, a tautomer, apharmaceutically-acceptable salt thereof, wherein: R¹ is NR⁵R⁵; R⁵ andR⁵ are taken together with the nitrogen atom to which they are attachedto form a 4- to 10-membered heterocycle substituted with 1-4 R⁷; R⁷, ateach occurrence, is independently selected from H, halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, OH, CF₃, and —NR⁸R⁸; and R⁸, at each occurrence, isindependently selected from H and C₁₋₄ alkyl.
 7. The compound of claim1, having Formula (V):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: M is selected from N and CR¹⁰; R¹ is a 5- to10-membered heterocycle substituted with 1-4 R⁷; R⁶, at each occurrence,is independently selected from H and C₁₋₄ alkyl; R⁷, at each occurrence,is independently selected from H, ═O, NO₂, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl),—(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂,—SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁸, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a),—(CHR¹⁰)_(n)CONR^(a)R^(a), —(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl),—O(CHR¹⁰)_(n)carbocycle, —O(CHR¹⁰)_(n)heterocycle,—O(CHR¹⁰)_(n)NR^(a)R^(a), and —(CR¹⁰R¹⁰)_(n)-4- to 10-memberedheterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle aresubstituted with 0-4 R^(b), R¹⁰ is selected from H and C₁₋₄ alkyl;R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle, wherein said alkyl, alkylene, andheterocycle are substituted with 0-4 R^(b), R^(b), at each occurrence,is independently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl),CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄alkyl), —R^(c), COR^(c), CO₂R, and CONHR^(c); R^(c), at each occurrence,is independently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halogen, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), and aheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; andp, at each occurrence, is independently selected from 0, 1, and
 2. 8.The compound of claim 7, having Formula (VI):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: R¹ is selected from

R⁶ is H; and R⁷, at each occurrence, is independently selected from H,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹.
 9. The compound of claim 1,having Formula (VII):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: M is selected from N and CR¹⁰; R⁵, at each occurrence,is independently selected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀carbocycle, and —(CR⁶R⁶)_(n)-4 to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p),wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4R⁷; alternatively, R⁵ and R⁵ are taken together with the nitrogen atomto which they are attached to form a 4- to 10-membered heterocyclesubstituted with 1-4 R⁷; R⁷, at each occurrence, is independentlyselected from H, ═O, NO₂, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃,—(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁ 4 alkyl), —NHCO₂(CH₂)₂O(C₁₋₄alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O(C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)C(O)NR^(a)R^(a), C(O)OC₁₋₄alkyl, C(O)O-carbocycle, C(O)O-heterocycle,SO₂alkyl, SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; R⁹, at eachoccurrence, is independently selected from halogen, OH, CN, NO₂, CHF₂,CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄alkyl), —(CHR¹⁰)_(n)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b); R¹⁰is selected from H and C₁₋₄ alkyl; R^(a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH, CO(C₁₋₄ alkyl),COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl),C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R^(c), and CONHR^(c);alternatively, R^(a) and R^(a) are taken together with the nitrogen atomto which they are attached to form a 4- to 10-membered heterocycle,wherein said alkyl, alkylene, and heterocycle are substituted with 0-4R^(b); R^(b), at each occurrence, is independently selected from ═O,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂,CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R, COR^(c), CO₂R^(c), andCONHR^(c); R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); R^(d),at each occurrence, is independently selected from ═O, halogen, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); n, at each occurrence, is independently selected from0, 1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 10. The compound of claim 9 or a stereoisomer, atautomer, a pharmaceutically-acceptable salt thereof, wherein: M is N;R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4- to 10-membered heterocycle selected from

wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R⁷;alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹, R⁹, at each occurrence, isindependently selected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —NH₂, and a 4- to10-membered heterocycle.
 11. The compound of claim 3, having Formula(VIII):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: M is selected from N and CH; R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂, F,Cl, Br, C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, CN, OH,CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCOH, —NHCO(C₁₋₄-alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl),—NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH,—NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H,—(CH₂)₁₋₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl), S(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹ and wherein said carbocycle is selected from

and wherein said heterocycle is selected from

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—NHC(O)C₁₋₄alkyl, C(O)O—C₁₋₄alkyl,C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle,SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)_(n)—C₃₋₆cycloalkyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heterocycle, wherein said alkyl,cycloalkyl, aryl, and heterocycle are substituted with 0-4 R⁹;alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁹, at each occurrence, is independently selected from F, Cl, Br, I, OH,═O, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄alkyl), CONH₂, —(CH₂)_(f)NR^(a)R^(a), —(CH₂)CONR^(a)R^(a),—(CH₂)_(n)NHCO(C₁₋₄ alkyl), —O(CH₂)_(n)heterocycle,—O(CH₂)₂₄NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-4- to10-membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b); R^(a), at each occurrence,is independently selected from H and C₁₋₄ alkyl; alternatively, R^(a)and R^(a) are taken together with the nitrogen atom to which they areattached to form a 4- to 10-membered heterocycle, wherein said alkyl,alkylene, and heterocycle are substituted with 0-4 R^(b); R^(b), at eachoccurrence, is independently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, OCF₃, OC(O)C₁₋₄ alkyl, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, and —NHCO₂(C₁₋₄ alkyl),wherein said alkyl and alkoxy are substituted with R^(d); R^(d), at eachoccurrence, is independently selected from ═O, halogen, —OH, C₁₋₄ alkyl,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl),and a heterocycle containing carbon atoms and 1-4 heteroatoms selectedfrom the group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n,at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and p, at each occurrence, is independently selected from 0, 1, and 2.12. The compound of claim 3 having Formula (VIII):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: M is selected from N and CH; R¹ is NR⁵R⁵; R⁵ and R⁵are taken together with the nitrogen atom to which they are attached toform a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, F, Cl, Br,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—NR⁵R⁵, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂,—(CH₂)_(n)—CONR⁸R⁸, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-heterocycleselected from

R⁸, at each occurrence, is independently selected from H, CF₃, CD₃, CH₃,C(CH₃)₃,

alternatively, R⁸ and R⁸ are taken together to form

and R⁹, at each occurrence, is independently selected from F, Cl, OH,NO₂, CHF₂, (CH₂)₀₋₂CF₃, CD₃, CH₃, OC₁₋₄ alkyl, SO₂NH₂, and phenylsubstituted with C₁₋₄ alkyl.
 13. The compound of claim 7 or astereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof,wherein: M is N; R¹ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —(CH₂)_(n)-carbocycle,and —(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkenyl,alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4R⁹; R⁸, at each occurrence, is independently selected from H and C₁₋₄alkyl; R⁹, at each occurrence, is independently selected from halogen,OH, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl),CO₂H, and CO₂(C₁₋₄ alkyl); n, at each occurrence, is independentlyselected from 0, 1, 2, 3, and 4; and p, at each occurrence, isindependently selected from 0, 1, and
 2. 14. The compound of claim 1,having Formula (IX):

or a stereoisomer, a tautomer, a pharmaceutically-acceptable saltthereof, wherein: R¹ is selected from NR⁵R⁵, and a 5- to 10-memberedheterocycle substituted with 1-4 R⁷; R³, at each occurrence, isindependently selected from halogen and C₁₋₆ alkyl; R⁵ and R⁵ are takentogether with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle substituted with 1-4 R⁷; R⁷, at eachoccurrence, is independently selected from H, ═O, NO₂, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁ 4alkyl), —NHCO₂(CH₂)₂O(C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O(C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁸, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)—C(O)NR^(a)R^(a),C(O)OC₁₋₄alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl,SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkenyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; R⁹, at each occurrence, isindependently selected from halogen, OH, CN, NO₂, CHF₂, CF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl),—(CHR¹⁰)NR^(a)R^(a), —(CHR¹⁰)_(n)CONR^(a)R^(a),—(CHR¹⁰)_(n)NR^(a)CO(C₁₋₄ alkyl), —O(CHR¹⁰)_(n)carbocycle,—O(CHR¹⁰)_(n)heterocycle, —O(CHR¹⁰)_(n)NR^(a)R^(a), and—(CR¹⁰R¹⁰)_(n)-4- to 10-membered heterocycle, wherein said alkyl,alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^(b); R¹⁰is selected from H and C₁₋₄ alkyl; R^(a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH, CO(C₁₋₄ alkyl),COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl),C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R^(c), and CONHR^(c);alternatively, R^(a) and R^(a) are taken together with the nitrogen atomto which they are attached to form a 4- to 10-membered heterocycle,wherein said alkyl, alkylene, and heterocycle are substituted with 0-4R^(b); R^(b), at each occurrence, is independently selected from ═O,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂,CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c); R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); R^(d),at each occurrence, is independently selected from ═O, halogen, —OH,C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and a heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p); n, at each occurrence, is independently selected from0, 1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom 0, 1, and
 2. 15. A pharmaceutical composition comprising one ormore compounds according to claim 1 and a pharmaceutically acceptablecarrier or diluent.
 16. A method of treating a disorder associated withaberrant Rho kinase activity, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 17. The method of claim 16, wherein said disorder is selectedfrom a cardiovascular disorder, a smooth muscle related disorder, afibrotic disease, an inflammatory disease, neuropathic disorders,oncologic disorders, and an autoimmune disorder.
 18. The method of claim17 wherein said cardiovascular disorder is selected from angina,atherosclerosis, stroke, cerebrovascular disease, coronary heartdisease, stroke, heart failure, systolic heart failure, diastolic heartfailure, diabetic heart failure, heart failure with preserved ejectionfraction, cardiomyopathy, myocardial infarction, left ventriculardysfunction, left ventricular dysfunction after myocardial infarction,peripheral vascular disease, stenosis, vasospasm, hypertension andpulmonary hypertension, cardiac hypertrophy, myocardial remodeling,myocardial remodeling after infarction and after cardiac surgery andvalvular heart diseases.